Chroman-substituted, tetrahydroquinoline-substituted and thiochroman-substituted heteroarotinoids as anti-cancer agents

ABSTRACT

Chemical compounds that inhibit cancer cell growth are provided. The compounds are heteroarotinoids and derivatives thereof with oxygen, nitrogen or sulfur in chroman systems, tetrahydroquinoline systems, and tetrahydrothiochroman systems.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of co-pending U.S. Ser. No. 16/549,337,filed Aug. 23, 2019, and claims the benefit of U.S. Provisional patentApplication Ser. No. 62/722,294, filed on Aug. 24, 2018, andincorporates said applications by reference into this document as iffully set out at this point.

TECHNICAL FIELD

The invention relates novel chemical agents that inhibit lung and humanovarian cancer cell growth e.g. via apoptosis, and their use asanticancer agents. The invention more specifically relates to certainheteroarotinoids and derivatives thereof with oxygen, nitrogen or sulfurin chroman systems, tetrahydroquinoline systems, andtetrahydrothiochroman systems.

BACKGROUND

Conventional therapy of advanced stage malignant ovarian cancer (MOC)achieves at best a modest improvement in survival rates. Unfortunately,approximately two thirds of women with ovarian cancer (OC) are diagnosedat an advanced stage (Stage IIIC or IV) [1], and a large proportion ofthese patients demonstrate chemoresistance. Moreover, those withrecurrent drug-resistant ovarian cancer show only 10-15% response rate.Very few treatment options are available, and those that are have onlymodest success. For example, for partially platinum-sensitive OC(recurrent OC), second-line chemotherapies include PLD andTrabectedin+PLD; and third-line treatments include platinum basedre-induction chemotherapy, hormonal treatment and therapies in clinicaltrials e.g. targeted agents combined with chemotherapy andintraoperative radiation (IORT) combined with intraoperativechemotherapy. However, limitations of these treatments include: thetherapeutic effects are generally lower than in women withplatinum-sensitive OC; the toxicity of conventional chemotherapy isdose-limiting toxicities; efficacy data is unknown for many therapiesbeing evaluated in clinical trials; and there is typically only minoruse of radiotherapy in recurrent ovarian cancer. For platinumresistant/refractory OC, treatment options include paclitaxel, PLD,topotecan; newer chemotherapy agents such as irinotecan, nanoparticles,albumin bound paclitaxel, and sagopilone; and therapeutic agentstargeting angiogenesis, PARP, PD-1/PD-L1, growth factor receptors.However, these treatments often result in a poor prognosis, and combinedchemotherapies increase toxicity (and severe side effects) with noenhancement of efficacy.

Heteroarotinoids have also been tested for anticancer activity. Examplesof heteroarotinoids and recent examples of heteroarotinoid anti-canceractivity can be found in several papers such as: Zacheis, D.; Dhar, A.;Lu, S.; Madler, M. M.; Klucik, J.; Brown, C. W.; Liu, S.; Clement, F.;Subramanian, S.; Weerasekare, G. M.; Berlin, K. D.; Gold, M. A.; Houch,Jr., J. R.; Fountain, K. R.; Benbrook, D. M. Heteroarotinoids inhibithead and neck cancer cell lines in vitro and in vivo through both RARand RXR retinoic acid receptors. J. Med. Chem. 1999, 42, 4434-4445;Guruswamy, S.; Lightfoot, S.; Gold, M.; Hassan, R.; Berlin, K. D.; Ivey,T. R.; Benbrook, D. M. Effects of retinoids on cancer phenotype andapoptosis in organotypic culture of ovarian carcinoma. J. NationalCancer Institute, 2001, 93, 20-29; Chun, K.-H.; Benbrook, D. M.; Berlin,K. D. Hong, W. K.; Lotan, R. Induction of apoptosis in head and necksquamous cell carcinoma (HNSCC) cell lines by heteroarotinoids through amitochondrial dependent pathway. Cancer Research 2003, 63, 3826-3832;Liu, S.; Brown, C. W.; Berlin, K D.; Dhar, A.; Guruswamy, S.; Brown, D.;Benbrook, D. M. Synthesis of flexible sulfur-containing heteroarotinoidsthat induce apoptosis and reactive oxygen species with discriminationbetween malignant and benign cells. J. Med. Chem. 2004, 47, 999-1007;Benbrook, D. M.; Kamelle, S. A.; Guruswamy, S. B.; Lightfoot, S. A.;Hannafon, B. N.; Rutledge, T. L.; Gould, N. S.; Dunn, S. T.; Berlin, K.D. Flexible heteroarotinoids (FLEX-HETS) exhibit improved therapeuticratios as anti-cancer agents over retinoic acid receptor agonists.Investigational New Drugs. 2005, 23, 417-428; Brown, C. W.; Liu, S.;Klucik, J.; Berlin, K. D.; Brennan, P. J.; Kaur, D.; Benbrook, D. M;Novel heteroarotinoids as potential antagonists of Mycobacterium bovisBCG. J. Med. Chem. 2004, 47, 1008-1017; Subramanian, S.; Smith, C. M.;Tabatabai, A.; Bryan, C. D.; Buettner, B.; Hale, S.; Wakefield, C. A.;Benbrook, D. M.; Berlin, K. D. Syntheses of novel heteroarotinoids withreceptor activation capabilities and TGase activity. Single crystalanalysis of(E)-4-[(2,3-dihydro-2,2,4,4-tetramethyl-2H-1-benzo[b]thiopyran-6-yl)-1-propenyl]-2-methylbenzoicacid. Phosphorus, Sulfur, and Silicon and The Related Elements. 2005,180, 67-77; Le, T. C.; Berlin, K. D.; Benson, S. D.; Nelson, A. C.;Benbrook, D. M.; Eastman, M.; Bell-Eunice, G. Unusual heteroarotinoidswith anti-cancer activity against ovarian cancer cells. Open MedicinalChemistry. 2007, 1, 11-23; Lin, Yi-D; Chen, S.; Yue, P.; Zou, W.;Benbrook, D. M.; Liu, S.; Le, T. C.; Berlin, K. D.; Khuri, F. R.; Sun,S.-Y. CAAT/enhancer binding protein homologous protein-dependent deathreceptor 5 induction is a major component of SHetA2-induced apoptosis inlung cancer cells. Cancer Res. 2008, 68, 5335-5344; Lin, Y.; Lui, X.;Yue, P.; Benbrook, D. M.; Berlin, K. D.; Khuri, F. R.; Sun, S.-Y.Involvement of C-flip and surviving down-regulation in flexibleheteroarotinoid-induced apoptosis in lung cancer cells. Molecular CancerTherapeutics. 2008, 7, 3556-3565; Liu, T.; Masamha, C. Chengedza, S.;Berlin, K. D.; Lightfoot, S.; He, F.; Benbrook, D. M. Development offlexible-heteroarotinoids (Flex-Hets) for kidney cancer. MolecularCancer Therapeutics. 2009, 8, 1227-1238; Nammalwar, B.; Bunce, R. A.;Benbrook, D. M.; Lu, T.; Li, Hui-Fang; Ya-Dong, C.; Berlin, K. D.Synthesis ofN-[3,4-dihydro-4-(acetoxymethyl)-2,2,4-trimethyl-2H-1-benzo-thiopyran-6-yl]-N′-(4-nitrophenyl)thioureaandN-[3,4-(dihydromethyl)-2,2,4-trimethyl-2H-1benzothiopyran-6-yl]-N′(4-nitrophenyl)-thiourea,a major metabolite ofN-{3,4-dihydro-2,2,4,4-tetramethyl-2H-1-benzothiopyran-6-yl)-N′-(4-nitrophenyl)thiourea.Phosphorus, Sulfur, and Silicon and The Related Elements. 2011, 186,189-204. Benbrook, D. M.; Nammalwar, B.; Long, A.; Matsumoto, H.; Singh,A.; Bunce, R. A.; Berlin, K. D. SHetA2 interference with mortalinbinding to p66she and p53 identified using drug-conjugate magneticmicrospheres. Investigational New Drugs. 2014, 32, 412-423;Gnanasekaran, K. K.; Benbrook, D. M.; Nammalwar, B.; Thavathiru, E.;Bunce, R. A.; Berlin, K. D. Synthesis and evaluation of secondgeneration Flex-Het scaffolds against the human ovarian cancer A2780cell line. Eur. Journal of Medicinal Chemistry, 2015, 96, 209-217; Liu,S.; Zhou, G.; Lo, S. N. H.; Louie, M.; Rajagopalan, V. SHetA2, A newcancer-preventive drug candidate, Chapter 3 in “Anti-Cancer DrugPreventive Drug Candidates”. InTech, 2016, DOI 10.5772/65365 (this areview); Sharma, A.; Benbrook, D. M.; Woo, S. Pharmacokinetics andinterspecies scaling of a novel, orally-bioavailable anti-cancer drug,SHetA2. PLOS, 2018, 13 (4) https://doi.org/10.1371; Mahjabeen, S.;Hatipoglu, M. K.; Chandra, V.; Benbrook, D. M.; Garcia-Contreras, L.Optimization of a vaginal suppository formulation to deliver SHetA2 as anovel treatment for cervical dysplasia. Journal of PharmaceuticalSciences. 2018, 107, 638-646.

The heteroarotinoid anticancer agent SHetA2 [CAS #NSC-726189,N-(2,3-dihydro-2,2,4,4-tetramethyl-6-benzothiopyranyl)-N-(4-nitrophenyl)urea],inhibits the growth of all 60 cancer cell lines that are available fromthe National Cancer Institute, and exhibits essentially no toxicitytoward normal tissues, no skin irritation, and does not cause birthdefects in animal studies. Several derivatives of SHetA2 have exhibitedstrong activity against Non-Small Cell Lung Cancer (NSCLC) [Yi-D Lin, S.Chen, P. Yue, W. Zou, D. et. al. Cancer Res. 2008, 68, 5335-5344. Y.Lin, X. Lui, P. Yue, D. M. Benbrook, et. al. Molecular CancerTherapeutics. 2008, 7, 3556-3565.] NSCLC is especially difficult totreat. Agents such as KEYTRUDA®, OPDIVO®, and ZYKADIA® are used but manyside effects occur with these clinical agents.

New anti-cancer agents that exhibit improved anti-cancer activitywithout causing deleterious side effects are needed.

Before proceeding to a description of the present invention, however, itshould be noted and remembered that the description of the inventionwhich follows, together with the accompanying drawings, should not beconstrued as limiting the invention to the examples (or embodiments)shown and described. This is so because those skilled in the art towhich the invention pertains will be able to devise other forms of thisinvention within the ambit of the appended claims.

SUMMARY

The present disclosure describes the synthesis and testing of newheteroarotinoids with chroman-, tetrahydroquinoline- orthiochroman-fused systems bonded to an aryl group via a urea or thiourealinker. The new compounds are the result of important chemicalimprovements that were made to the structure of the known anticanceragent SHetA2 in order to enhance its biological activity. For example,incorporation of a chroman (oxygen-atom at position 1) ortetrahydroquinoline (nitrogen atom at position 1) is a new uniquetransformation in this class of heterocycles. The new compoundsexhibited a range of major cancer inhibitory activities, depending onthe substitutions of [NO₂, CF₃, OCF₃] the aryl group attached to thelinker. The presence of geminal diethyl groups at C-1 and C-4 in thechroman unit appeared to contribute favorably to activity. Without beingbound by theory, it is believed that the linkers give more flexibilityfor docking to the protein mortalin, which is believed to be the targetreceptor and to be involved in the progress of a cell becomingcancerous. And, advantageously, it is well known that urea derivativesare easily handled by the body so that the new compounds will behavesimilarly and, as noted with SHetA2, are metabolized in a similarmanner. Among these new compounds, 32 compounds outperformed SHetA2 inthe inhibition of human A2780 ovarian cancer cells, and 19 of thesecompounds further exhibited improved potency (measured in half-maximalinhibitory concentration, IC₅₀). Several of the best compounds achieved92-95% efficacy (measured in growth inhibition) and 2 μM IC₅₀, whichwere better than SHetA2 (84%, 3 μM). The new compounds are expected tobe effective in other cancer cell lines and to have low toxicity innormal cells.

It is an object of the disclosure to provide a compound of Formula I

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl;    -   Y is O or S; and    -   Z is an optionally substituted phenyl, optionally substituted        phenylamino or optionally substituted benzylamide;        and salts, solvates and hydrates thereof,        with the caveat that the compound is not ShetA2 with the formula

In some aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl;    -   Y is O or S;    -   n is 0, 1, 2, 3, or 4; and    -   R₇ to R₁₁ are independently selected from a group consisting of        hydrogen, halogen, CN, NO₂, OH, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted haloalkyl,        optionally substituted haloalkoxy, ester or sulfonamide;        and salts, solvates and hydrates thereof.

In other aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅, R₆ and R₁₂ are hydrogen or optionally substituted C1-C5        alkyl;    -   Y is O or S; and    -   R₇ to R₁₁ are independently selected from a group consisting of        hydrogen, halogen, CN, NO₂, OH, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted haloalkyl,        optionally substituted haloalkoxy, ester or sulfonamide;        and salts, solvates and hydrates thereof.

In yet further aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅, R₆ and R₁₂ are hydrogen or optionally substituted C1-C5        alkyl;    -   Y is O or S; and    -   R₇ to R₁₁ are independently selected from a group consisting of        hydrogen, halogen, CN, NO₂, OH, optionally substituted alkyl,        optionally substituted alkoxy, optionally substituted haloalkyl,        optionally substituted haloalkoxy, ester or sulfonamide;        and salts, solvates and hydrates thereof.

In yet additional aspects, R₇, R₈, R₁₀, R₁₁ are hydrogen and R₉ ishydrogen, CF₃, OCF₃, CN, Cl, OCH₃ or OH.

In further aspects, R₇, R₉, R₁₀, R₁₁ are hydrogen and R₈ is CF₃, OCF₃,CN, Cl, OCH₃ or OH.

In yet further aspects, R₇, R₉, R₁₁ are hydrogen and R₈, R₁₀ are CF₃,OCF₃, CN, Cl, OCH₃ or OH.

In some aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are hydrogen, CH₃ or C₂H₅;    -   R₃ and R₄ are CH₃ or C₂H₅;    -   Y is O or S;    -   R₉ is CF₃, OCF₃, CN, Cl, OCH₃ or OH        and salts, solvates and hydrates thereof.

In additional aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are hydrogen, CH₃ or C₂H₅;    -   R₃ and R₄ are CH₃ or C₂H₅;    -   Y is O or S;    -   R₉ is CF₃, OCF₃, CN, Cl, OCH₃ or OH        and salts, solvates and hydrates thereof.

In yet other aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are hydrogen, CH₃ or C₂H₅;    -   R₃ and R₄ are CH₃ or C₂H₅;    -   Y is O or S;    -   R₉ is CF₃, OCF₃, CN, Cl, OCH₃ or OH    -   R₁₃ is H or CH₃;        and salts, solvates and hydrates thereof.

In even further aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are hydrogen, CH₃ or C₂H₅;    -   R₃ and R₄ are CH₃ or C₂H₅;    -   Y is O or S;    -   R₉ is CF₃, OCF₃, CN, Cl, OCH₃ or OH        and salts, solvates and hydrates thereof.

In some aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are hydrogen, CH₃ or C₂H₅;    -   Y is O or S; and    -   R₉ is CF₃, OCF₃, CN, Cl, OCH₃ or OH;        and salts, solvates and hydrates thereof.

In additional aspects, the compound has a formula:

wherein,

-   -   R₁ and R₂ are hydrogen, CH₃ or C₂H₅;    -   Y is O or S; and    -   R₇ to R₁₁ are independently selected from a group consisting of        hydrogen, CF₃, OCF₃, CN, Cl, OCH₃ or OH;        and salts, solvates and hydrates thereof.

In further aspects, the compound is elected from:

-   1-(4-Nitrophenyl)-3-(2,2,4,4-tetramethylchroman-6-yl)thiourea;-   Ethyl 4-(3-(2,2,4,4-Tetramethylchroman-6-yl)thioureido)benzoate;-   1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;-   4-(3-(2,2,4,4-Tetramethylchroman-6-yl)thioureido)benzenesulfonamide;-   1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylchroman-6-yl)urea;-   1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;-   1-(4-Nitrophenyl)-3-(4,4-dimethylchroman-6-yl)thiourea;-   1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;-   1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea;-   1-(4-Nitrophenyl)-3-(4,4-dimethylchroman-6-yl)urea;-   (4,4-Dimethylchroman-6-yl)-3-[4-trifluoromethyl)phenyl]urea;-   1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;-   1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-nitrophenyl)thiourea;-   1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-nitrophenyl)urea;-   1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-nitrophenyl)thiourea;-   1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;-   1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-nitrophenyl)urea;-   1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   1-(4-Nitrophenyl)-3-(2,2,4,4-tetraethylchroman-6-yl)thiourea;-   1-(4-Nitrophenyl)-3-(2,2,4,4-tetraethylchroman-6-yl)urea;-   1-(2,2,4,4-Tetraethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   1-(2,2,4,4-Tetraethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;-   1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)urea;-   1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)thiourea;-   1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;-   1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)-thiourea;-   1,1,4,4-Tetramethyl-6-(3-(4-nitrophenyl)ureido)-1,2,3,4-tetrahydroquinolin-1-ium    iodide;-   1-(4-Nitrophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea;-   1-(4-Nitrophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiourea;-   1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)-phenyl)urea;-   1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-trifluoromethyl)-phenyl)thiourea;-   1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)-phenyl)urea;-   1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)-phenyl)thiourea;-   1-(4-Aminophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea;-   3-(1,2,2,4,4-Pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(4-nitrophenyl)thiourea;-   1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)-urea;-   1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)-thiourea;-   1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methyl)phenyl)urea;-   1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methyl)phenyl)thiourea;-   1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methoxy)phenyl)urea;-   1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoro-methoxy)phenyl)thiourea;-   1-(4-Acetylphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;-   1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;-   1-(2-Methoxy-4-nitrophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;-   1-Phenyl-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(4-Methylphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(5,6,7,8-Tetrahydronaphthalen-2-yl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   4.3.4.    1-(4-Chlorophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea;-   4.3.7.    1-(3-Nitrophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   4.3.8.    1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(2-(trifluoromethyl)phenyl)thiourea;-   4-(3-(2,2,4,4-Tetramethylthiochroman-6-yl)thioureido)benzamide;-   1-(4-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(3-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(4-Hydroxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(3-Hydroxy-4-methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1,3-Bis(2,2,4,4-Tetramethylthiochroman-6-yl)thiourea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea;-   1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)urea;-   1-(4-Chlorophenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea;-   4-(3-(2,2,4,4-Tetramethylthiochroman-6-yl)thioureido)benzamide;-   1-(4-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(3-Methoxyphenyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-Benzyl-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-Phenethyl-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(4-Chlorobenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(4-Nitrobenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(2,2,4,4-Tetramethylthiochroman-6-yl)-3-(4-(trifluoromethyl)benzyl)thiourea;-   1-(4-Methoxybenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   1-(4-Hydroxybenzyl)-3-(2,2,4,4-tetramethylthiochroman-6-yl)thiourea;-   2-Phenyl-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;-   2-Benzoyl-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;-   2-(4-Nitrobenzoyl)-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;-   N-(2,2,4,4-Tetramethylthiochroman-6-yl)-2-(4-(trifluoromethoxy)benzoyl)hydrazine-1-carbothioamide;-   2-(3,5-Bis(trifluoromethyl)benzoyl)-N-(2,2,4,4-tetramethylthiochroman-6-yl)hydrazine-1-carbothioamide;-   4,4-Dimethylthiochroman-6-amine hydrochloride;    and salts, solvates and hydrates thereof.

In further aspects, the compound is:

The disclosure also provides methods of treating cancer in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of compound of Formula I

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl;    -   Y is O or S; and    -   Z is an optionally substituted phenyl, optionally substituted        phenylamino or optionally substituted benzylamide;        and salts, solvates and hydrates thereof, with the caveat that        the compound is not SHetA2 with the formula

In certain aspects, the compound is:

In further aspects, the cancer is ovarian cancer or small cell lungcancer.

The disclosure also provides a method of killing cancer cells,comprising contacting the cancer cells with an amount of a compound ofFormula I

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl;    -   Y is O or S; and    -   Z is an optionally substituted phenyl, optionally substituted        phenylamino or optionally substituted benzylamide;        and salts, solvates and hydrates thereof,

wherein the amount is sufficient to kill the cancer cells, and with thecaveat that the compound is not SHetA2 with the formula

In some aspects, the compound is:

In certain aspects, the cancer cells are ovarian cancer cells.

The foregoing has outlined in broad terms some of the more importantfeatures of the invention disclosed herein so that the detaileddescription that follows may be more clearly understood, and so that thecontribution of the instant inventors to the art may be betterappreciated. The instant invention is not to be limited in itsapplication to the details of the construction and to the arrangementsof the components set forth in the following description or illustratedin the drawings. Rather, the invention is capable of other embodimentsand of being practiced and carried out in various other ways notspecifically enumerated herein. Finally, it should be understood thatthe phraseology and terminology employed herein are for the purpose ofdescription and should not be regarded as limiting, unless thespecification specifically so limits the invention.

DETAILED DESCRIPTION

While this invention is susceptible of embodiment in many differentforms, there is shown in the drawings, and will herein be describedhereinafter in detail, some specific embodiments of the instantinvention. It should be understood, however, that the present disclosureis to be considered an exemplification of the principles of theinvention and is not intended to limit the invention to the specificembodiments or algorithms so described.

The new heteroarotinoids disclosed herein comprise a chroman-,tetrahydroquinoline- or thiochroman-fused ring system bonded to an arylgroup via a urea or thiourea linker (Formula I). It is well known thaturea derivatives are easily handled by the body and exhibit lowtoxicity. Insertion of a chroman (oxygen-atom at position-1) ortetrahydroquinoline (nitrogen atom at position-1) is a new uniquestructural change in this family of heterocycles. In addition, compoundswith specific substituents [e.g. NO₂, CF₃, OCF₃] bonded to a singlephenyl ring attached to the linker displayed major cancer inhibitoryactivity. The presence of geminal diethyl groups at C-1 and C-4 in thetetrahydroquinoline unit appeared to contribute to maximum activity.

The disclosed heterocycles exhibit a range of abilities to inhibit thegrowth of human lung and A2780 ovarian cancer cells. In fact, several ofthe disclosed compounds outperformed SHetA2 in the inhibition of A2780cells, and some exhibited very high potency. For example, several of thebest compounds achieved 92-95% efficacy (measured in growth inhibition)and 2 μM IC₅₀, i.e. better than SHetA2, which has about 84% efficacy and3 μM IC₅₀. The compounds are able to inhibit growth of all 60 cancercell lines available from the National Cancer Institute yet thesecompounds do not cause toxicity or skin irritation in normal tissues,and do not cause birth defects in animal studies. Without being bound bytheory, it is believed that the linkers render the new compounds moreflexible for docking to the protein mortalin, which is believed to bethe target receptor and is believed to be involved in the progress of acell becoming cancerous. In binding to mortalin, it is believed that thecompounds induce normal differentiation or apoptosis of the cancerouscells.

A generic structure of the heteroarotinoids is shown in Formula 1 below.

wherein,

-   -   R₁ and R₂ are optionally C1-C5 substituted alkyl;    -   R₃ and R₄ are optionally C1-C5 substituted alkyl;    -   G is CH₂, C═O or CHOH;    -   X is S, O, NR or N⁺(R)₂ where R is hydrogen or an optionally        substituted C1-C5 alkyl;    -   R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl;    -   Y is O or S; and    -   Z is an optionally substituted phenyl, optionally substituted        phenylamino or optionally substituted benzylamide;        and salts, solvates and hydrates thereof,        with the caveat that the compound is not SHetA2 with the formula

The salts may be a pharmaceutically acceptable salts. Stereoisomers ofthe compounds are also encompassed.

In general, the compounds can be divided into three categories:chroman-containing heteroarotinoids, tetrahydroquinoline-containingheteroarotinoids and thiochroman-containing heteroarotinoids, exemplaryformulations of which are:

Choman-Containing Heretoarotinoids

Tetrahydroquinoline-Containing Heretoarotinoids

Tetrahydrothiochroman-Containing Heretoarotinoids

As used herein, “a compound of the invention” includes all salts,solvates, complexes, polymorphs, radiolabeled derivatives, tautomers,stereoisomers and optical isomers of the compounds of Formula I.

The term “solvate” as used herein refers to an aggregate that comprisesone or more molecules of a compound of the disclosure with one or moremolecules of solvent. Examples of solvents that form solvates include,but are not limited to, water, isopropanol, ethanol, methanol, DMSO,ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refersto the aggregate or complex where the solvent molecule is water. Thesolvent may be an inorganic solvent such as for example water in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent, such as ethanol. Thus, the compounds of the presentdisclosure may exist as a hydrate, including a monohydrate, dihydrate,hemihydrate, sesquihydrate, trihydrate, tetrahydrate or the like, aswell as the corresponding solvated forms. The compound of the disclosuremay be true solvates, while in other cases, the compound of thedisclosure may merely retain adventitious water or be a mixture of waterplus some adventitious solvent.

Compositions/Pharmaceutical Compositions

Compositions, which may be pharmaceutical compositions, comprising oneor more of the compounds disclosed herein as provided. Such compositionsgenerally comprise at least one of the disclosed compounds, i.e., one ormore than one (a plurality) of different compounds (e.g. 2 or more suchas 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) may be included in a singleformulation. Pharmaceutical compositions generally include one or moresubstantially purified compounds as described herein, typically preparedusing pharmaceutically acceptable excipients. As used herein, the term“pharmaceutically acceptable” refers to those compounds, materials,compositions, and dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

As used herein, “pharmaceutically acceptable excipients” includes alldiluents, carriers binders, glidants and other components ofpharmaceutical formulations with which the compound of the invention isadministered. A pharmacologically suitable or acceptable(physiologically compatible) carrier may be, for example, aqueous oroil-based.

In some aspects, such compositions are prepared as liquid solutions orsuspensions, or as solid forms such as tablets, pills, powders and thelike. Solid forms suitable for solution in, or suspension in, liquidsprior to administration are also contemplated (e.g. lyophilized forms ofthe compounds), as are emulsified preparations. In some aspects, theliquid formulations are aqueous or oil-based suspensions or solutions.In some aspects, the active ingredients are mixed with excipients whichare pharmaceutically acceptable and compatible with the activeingredients, e.g. pharmaceutically acceptable salts. Suitable excipientsinclude, for example, water, saline, dextrose, glycerol, ethanol and thelike, or combinations thereof. In addition, the composition may containminor amounts of auxiliary substances such as wetting or emulsifyingagents, pH buffering agents, preservatives, and the like. If it isdesired to administer an oral form of the composition, variousthickeners, flavorings, diluents, emulsifiers, dispersing aids orbinders and the like are added. The composition of the present inventionmay contain any such additional ingredients so as to provide thecomposition in a form suitable for administration. The final amount ofcompound in the formulations varies, but is generally from about 1-99%.Still other suitable formulations for use in the present invention arefound, for example in Remington's Pharmaceutical Sciences, 22nd ed.(2012; eds. Allen, Adejarem Desselle and Felton).

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins (such as humanserum albumin), buffer substances (such as twin 80, phosphates, glycine,sorbic acid, or potassium sorbate), partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes (such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, or zinc salts), colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, methylcellulose,hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucoseand sucrose; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil;corn oil and soybean oil; glycols; such a propylene glycol orpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

“Pharmaceutically acceptable salts” refers to the relatively non-toxic,inorganic and organic acid addition salts, and base addition salts, ofcompounds of the present invention. These: salts can be prepared in situduring the final isolation and purification of the compounds. Inparticular, acid addition salts can be prepared by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Exemplary acidaddition salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactiobionate, sulfamates, malonates,salicylates, propionates, methylene-bis-.beta.-hydroxynaphthoates,gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates and laurylsulfonate salts, and the like. See, forexample S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66,1-19 (1977) which is incorporated herein by reference. Base additionsalts can also be prepared by separately reacting the purified compoundin its acid form with a suitable organic or inorganic base and isolatingthe salt thus formed. Base addition salts include pharmaceuticallyacceptable metal and amine salts. Suitable metal salts include thesodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts.The sodium and potassium salts are preferred. Suitable inorganic baseaddition salts are prepared from metal bases which include sodiumhydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinchydroxide and the like. Suitable amine base addition salts are preparedfrom amines which have sufficient basicity to form a stable salt, andpreferably include those amines which are frequently used in medicinalchemistry because of their low toxicity and acceptability for medicaluse. ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine, diethylamine,piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammoniumhydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, e.g., lysine andarginine, and dicyclohexylamine, and the like.

Methods

The present disclosure encompasses methods of treating cancer, in asubject or patient in need thereof, using one or more of the compoundsdisclosed herein. Generally, the methods involve administering to thesubject one or more of the disclosed compounds (generally present in apharmaceutically acceptable carrier), in an amount sufficient to treatthe cancer, e.g. by killing cancer (e.g. tumor) cells which come intocontact with the administered compound within the body of the subject.Methods of administration are discussed in detail below. In some cases,treatment with the compounds will effect a cure of the cancer, i.e. alltumor cells will be killed and/or eradicated from the body of thesubject. However, those of skill in the art will recognize that muchbenefit may be derived even if a complete cure is not attained. Forexample, the growth of a tumor may be stopped or slowed, the progressionof the cancer may be halted or slowed, the life of the cancer patientmay be extended or improved, one or more symptoms of the cancer may beameliorated, etc.

The present disclosure also encompasses methods of killing cancer cellswith the compounds disclosed herein. The cancer cells may be in vivo orin vitro. Generally, the methods involve contacting the cancer cellswith one or more of the disclosed compounds, in an amount sufficient tokill the cancer cell. Without being bound by theory, the mechanism ofkilling may be via apoptosis of the cancer cell.

Administration

The compounds may be administered in vivo by any suitable routeincluding but not limited to: orally; by injection (e.g. intravenous,intraperitoneal, intramuscular, subcutaneous, intra-aural,intraarticular, intramammary, intratumorally and the like); byabsorption through epithelial or mucocutaneous linings (e.g., nasal,oral, vaginal, rectal, gastrointestinal mucosa, and the like); etc. Inpreferred embodiments, the mode of administration is oral or byinjection.

In addition, the compositions may be administered in conjunction withother treatment modalities such as: other anticancer agents, painmedications, substances that boost the immune system, variouschemotherapeutic agents, anti-nausea medications, appetite enhancers,antibiotic agents, and the like. The compounds may also be used incancer treatment protocols that also include e.g. surgery, radiationtherapy, etc.

The amount of a compound that is administered to an individual (who isusually a mammal, and may be a human) will vary based on severalfactors, as will be understood by those of skill in the art. Forexample, the dose and frequency of administration may vary according tothe gender, age, weight, general physical condition, ethnic background,etc. of the individual, as well as whether or not the individual hasother diseases or conditions that might impinge on the treatment.Generally, the dose for a therapeutically effective amount will be inthe range of from about 0.01 to about 100 mg/kg of body weight, such asabout 0.1, 0.5, 1.0, 5.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95 or 100 mg/kg of body weight.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of one or moresymptoms a disease, disorder, or side effect, or a decrease in the rateof advancement of a disease or disorder. The term also includes withinits scope amounts effective to enhance normal physiological function. Atherapeutically effective amount is generally an amount thatameliorates, lessens or improves at least one symptom of thedisease/condition that is being treated, and this amount may alsoeradicate all symptoms of the disease/condition, i.e. it may cure thesubject of the disease/condition. In particular, the subject may becomeentirely cancer free and/or the life of the subject may be extended.

While the subjects that are treated are often humans, veterinaryapplications of the treatment methods are also encompassed, especiallyfor companion pets such as dogs, cats, etc.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient, vehicle or carrier. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions.

Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Such unit doses may therefore be administered once or more than once aday. Such pharmaceutical compositions may be prepared by any of themethods well known in the pharmacy art.

Types and Stages of Cancer that are Treated

The compounds disclosed herein can be used to treat any type ofproliferative diseases, i.e. a disease caused by or associated withover-proliferation, such as a cancer and/or pre-cancerous syndromes,including metastatic cancers such as metastatic tumors. Examples oftypes of cancer that can be treated include but are not limited to:Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma,AIDS-Related Lymphoma, Primary CNS Lymphoma, Anal Cancer, AppendixCancer, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Central NervousSystem, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, BoneCancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and MalignantFibrous Histiocytoma, Brain Stem Glioma, Brain Tumor (e.g. Astrocytomas,Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous SystemAtypical Teratoid/Rhabdoid Tumor, Central Nervous System EmbryonalTumors, Central Nervous System Germ Cell Tumors, Craniopharyngioma,Ependymoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma,Carcinoid Tumor, Gastrointestinal, Cardiac (Heart) Tumors, CentralNervous System (e.g. Atypical Teratoid/Rhabdoid Tumors, EmbryonalTumors, Germ Cell Tumors, Lymphomas), Cervical Cancer, ChildhoodCancers, Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia(CLL), Chronic Myelogenous Leukemia (CML), Chronic MyeloproliferativeNeoplasms, Colon Cancer, Colorectal Cancer, Craniopharyngioma, CutaneousT-Cell Lymphoma, Ductal Carcinoma In Situ (DCIS), Embryonal Tumors,Endometrial Cancer, Ependymoma, Esophageal Cancer,Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumors,Extragonadal Germ Cell Tumors, Eye Cancer, Intraocular Melanoma,Retinoblastoma, Fallopian Tube Cancer, Fibrous Histiocytoma of Bone,Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach)Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal StromalTumors (GIST), Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer,Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, HodgkinLymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet CellTumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney (RenalCell, Wilms Tumor and Other Childhood Kidney Tumors), Langerhans CellHistiocytosis, Laryngeal Cancer, Leukemia (Acute Lymphoblastic (ALL),Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous(CML), Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary),Lung Cancer (Non-Small Cell, Small Cell), Lymphoma, Macroglobulinemia,Waldenström—see Non-Hodgkin Lymphoma, Malignant Fibrous Histiocytoma ofBone and Osteosarcoma, Melanoma, Intraocular (Eye), Merkel CellCarcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer withOccult Primary Mouth Cancer, Multiple Endocrine Neoplasia Syndromes,Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides,Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms,Myelogenous Leukemia, Chronic (CIVIL), Myeloid Leukemia, Acute (AML),Myeloma, Multiple, Myeloproliferative Neoplasms, Chronic, Nasal Cavityand Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma,Non-Hodgkin Lymphoma, Oral Cancer, Oral Cavity Cancer, Lip andOropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma ofBone, Ovarian Cancer, Epithelial, Germ Cell Tumor, Low MalignantPotential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors(Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus andNasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, PharyngealCancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/MultipleMyeloma, Pleuropulmonary Blastoma, Primary Central Nervous System (CNS)Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer,Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional CellCancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma(Ewing, Kaposi, Osteosarcoma, Rhabdomyosarcoma, Soft Tissue, Uterine),Sézary Syndrome, Skin Cancer, Small Intestine Cancer, Squamous CellCarcinoma, Squamous Neck Cancer with Occult Primary, Metastatic Stomach(Gastric) Cancer, T-Cell Lymphoma, Cutaneous, Testicular Cancer, ThroatCancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Ureter and RenalPelvis Cancer, Transitional Cell Cancer, Urethral Cancer, UterineCancer, Vaginal Cancer, Vulvar Cancer, and Wilms Tumor.

The cancer may be at any stage. Current practice is to assign a numberfrom I to IV to a cancer, with I being an isolated cancer and IV being acancer which has spread to the limit of what the assessment measures.The stage generally takes into account the size of a tumor, whether ithas invaded adjacent organs, how many regional (nearby) lymph nodes ithas spread to (if any), and whether it has appeared in more distantlocations (metastasized).

In some aspects, the cancer is ovarian cancer (OC), such as advancedstage OC (e.g. stage II, III or IV). In other aspects, one or more ofthe compounds described herein is/are used to treat cancer that isrefractory to other cancer treatments (i.e. does not respond totreatment with a particular agent or combination of agents), and/or acancer that has become resistant to other treatments (e.g. the cancerresponded when treatment was initiated but stops responding, recurs,etc.) It is highly advantageous to have available a plurality ofdifferent compounds as described herein, for use, together orsequentially, to treat cancers.

The present compounds can be administered in conjunction with (e.g. atthe same time as, or coordinated with) other cancer treatments. Forexample, a subject who is treated as described herein may also receiveor undergo, or may have already received or undergone, one or more ofradiation therapy, resection surgery, administration of otherchemotherapy agents, etc. Other chemotherapy agents are known in the artand include those disclosed, for example, in issued U.S. Pat. No.10,364,266, the complete contents of which is herein incorporated byreference.

The compounds may also be used in method of inducing normaldifferentiation and/or apoptosis of cancer cells (e.g. tumor cells).Apoptosis results in the death or killing of the cancer cells.Generally, such methods include a step of contacting the cancer cellswith an amount of the compound of Formula I, the amount being sufficientto induce one or both of normal differentiation and/or apoptosis ofcancer cells. The cancer cells may be in vitro (e.g. in an experimentallaboratory setting) or in vivo (e.g. present in the body of a subjectwith cancer, such as present in a tumor).

Synthesis of Compounds

Schemes 1-3 below provide an overview of the synthetic schemes used tosynthesize the compounds described herein. Details of each type ofsynthesis are provided in Example 1.

The present invention will be further understood with reference to thefollowing, non-limiting experimental examples.

EXAMPLES Example 1. Overview

This Example provides an overview of the steps and mechanisms involvedin the reactions to generate the compounds, illustrated in Schemes 4-15.

General procedure to obtain members of 2 and 3; Scheme 4. Conversion ofphenol (14) to phenyl 3,3-dimethylacryate 15 and then to 16 followednormal procedures. Known 16 was treated with a small excess ofmethyllithium as shown to give 17. The remaining sequence of17→18→19/20→21→2 and 3 followed, with 2 and 3 being formed in goodyields. The mixture of 19/20 could not be separated and thus was reducedto the amines from which 21 was isolated and purified. All products weresolids with sharp melting points and gave the expected analytical datafrom IR, NMR, and elemental analyses.

Members of 4 and 5 in Scheme 5 were also obtained by similarmethodology. Utilizing 16 as starting material, the remaining steps arecommon and known by those skilled in the art, but not as applied herein.The nitration step gave two isomers 24/25 which could not be separated,but reducing the nitro group to the amino group gave two isomers (26,27) that were separable. The reducing mixture of Fe/NH₄Cl converted 24and 25 to 26 and 27 in good yields. Isolation of 26 followed bytreatment with a small excess of the corresponding isocyanate orisothiocyanate gave members of 4 and 5 as solids with sharp meltingpoints and the expected IR and NMR analytical data along with elementalanalysis.

Schemes 6 and 7 led to 6 and 7, respectively, via similartransformations as above. In Scheme 6, a major change is the use ofethylmagnesium bromide to introduce ethyl groups at C-2. The other stepsare similar to those illustrated previously. In Scheme 7, the requiredintroduction of the geminal diethyl group at C-4 necessitated the acylstep to form 34 from phenol prior to closing of the ring to generate 35.The remaining steps are similar to those given to produce 2 and 3 andyielded members of 7. Members of 6 and 7 were solids, had sharp meltingpoints, and provided the expected IR, NMR, and elemental analysis datafor structural confirmation.

Scheme 8 required the starting material 35 which allowed theintroduction of two sets of geminal diethyl groups at C-2 and C-4 asillustrated. Again the remaining transformations paralleled thosepreviously described for 2 and 3 and led to members of 8. Final products8 in Scheme 8 were solids with sharp melting points. To further confirmthe structures, the products were purified by chromatography, and allproducts were identified by IR, NMR, and elemental analyses.

Schemes 9-11 describe the syntheses of tetrahydroquinoline members 9through 14. The procedures given are not to be considered limited to theapproaches shown, but may be available by a number of different ways.The phraseology and methodology given below is not limited to thatoutlined. Target compounds are delineated for thetetrahydroquinoline-containing systems 9-14. The heteroarotinoids 9,with one geminal dimethyl group at C-4 and a N—CH₃ group, allowed anassessment of the significance of the presence of these two groups onactivity. The conversion of 4-bromoaniline (47) to 48, followed by thesequence 48→49→50→51→52→53→54→9→10, led to 9 and 10 in good yields. Thesteps are reasonable but reaction conditions are specific for bestresults. Salt 10 was obtained by simple N-methylation of 9. Members ofboth 9 and 10 were solids and gave the appropriate IR, NMR, andelemental analyses.

Generation of the tetrahydroquinoline-containing series 11 (Scheme 10)progressed utilizing special conditions for each step with methodsfamiliar to someone skilled in the art of synthesis but have not beenpreviously utilized as illustrated. Starting with 4-bromoaniline (47),conversions of 55→56→57␣58→59→60→11 gave good yields. Formation of 11involved adding the required isocyanate or isothiocyanate in THF to 60in the normal manner. All members of 11 were solids with sharp meltingpoints and were structurally confirmed by IR, NMR, and elementalanalyses.

Scheme 11 displays the sequence to 12 starting with ethyl isobutyrate ina series of steps involving 61→62→63→64→65→66→67→68→69→12. Individualconversions followed common methods but required special conditions.Intermediates 61, 62, 63, 64, and 65 were light oils that were purifiedby distillation, while the succeeding members 66, 67, 68, and 69 weresolids or semi-solids. Compound 12 was a high melting solid identifiedby IR, NMR and elemental analysis, and all preceding intermediates werealso confirmed by IR and NMR analysis. Compound 12 is the counterpart ofstandard SHetA2 with the exception that the former has an N—CH₃ groupwhile the latter has an S atom in ring A.

Preparation of Members of Series 13.

Members of 13 were prepared in a normal manner as shown in Scheme 12.Reduction of the carbonyl group in 60 led to the secondary alcohol 70which was a brown oil that was quickly converted to members of 13. Allmembers of 13 were solids, melted sharply and were supported by IR, NMR,and the correct elemental analyses. Compounds 13 possessed the hydroxylgroup which can H-bond with proteins, including mortalin.

In order to obtain members of 14, it was necessary to develop thesynthesis of 76 as illustrated in Scheme 13 below. When carefullyexecuted, the individual steps in the sequence 70→71→73→74→75→76 wereaccomplished in good yields. Condensing known 4-acetamidothiophenol with71 in the first step was important for obtaining 72 in high yield.

Utilizing the key intermediate 77, the free base of 75, members of 14could be realized. The one-step process in Scheme 14 involved acondensation of 77 with a variety of isocyanates and isothiocyanates togenerate a variety of substituted members of 14.

Compound 14v required a special method as illustrated in Scheme 15.Reacting 4-acetamidothiphenol with 1-bromo-3-methylbut-2-ene gaveintermediate 78. The remaining steps followed standard procedures. Theyellow solid 14v gave the proper spectral and elemental analysis.

Example 2. Experimental Procedures and Results for Testing of theCompounds

The following explanation of experimental procedures employed toevaluate the compounds of this invention and results obtained therefromwill serve to further illustrate the value of the invention and theutility of the inventive compounds.

Method for Growth Inhibition Assay

To illustrate the general activity of the compounds inhibiting growth ofhuman A2480 ovarian cancer cells, selected compounds were synthesizedand evaluated. The compounds were dissolved in DMSO at a concentrationof 0.01 M. The human ovarian cancer cell line A2780 was plated in96-well tissue culture dishes at a concentration of 3000 cells per wellin RPMI medium supplemented with 10% fetal bovine serum and a mixture ofantibiotics and antimycotics. The next day, the cultures were treated intriplicate with compound concentrations ranging from 2 μM to 8 μMincrements. For compound 12, additional experiments were performed withconcentrations of 10 μM and a series of two-fold dilutions to 156 nM.Control cultures were treated with DMSO solvent only. After 72 h ofincubation, the CELLTITER 96® Non-Rad Cell Proliferation Assay (Promega)was used to quantify the remaining metabolically living cells. Aftersubtracting blank values, the optical density (OD) readouts of the assayfor the treated cultures were normalized with the average OD of thecontrol cultures. For each compound, the experiment was repeated atleast once, resulting in a minimum of 6 dose-response curves. ForSHetA2, 24 response curves were available for statistical fittingparameters. A custom program was written in GNU Octave, a free softwarecompatible with Matlab, to fit the dose-response curves with afour-parameter sigmoid function, extracting the IC₅₀ and efficacy (themaximal % growth inhibition) parameters.

Theoretical Docking Methods

AutoDock 4.2 [G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K.Belew, D. S. Goodsell, A. J. Olson, AutoDock4 and AutoDockTools4:Automated docking with selective receptor flexibility, J. Comput. Chem.,30 (2009) 2785-2791] was used to dock the compounds to the substratebinding domain of mortalin (Protein Data Bank ID: 3N8E). For thecompounds, ChemSketch™ (Advanced Chemistry Development, Inc. ADC/Labs,Toronto, Canada) was used to generate the SMILES notations, which weresubsequently converted to PDB files with initial three-dimensionalcoordinates using OpenBabelGUI [N. M. O'Boyle, M. Banck, C. A. James, C.Morley, T. Vandermeersch, G. R. Hutchison, OpenBabel: An open chemicaltoolbox, J. Cheminform., 3 (2011) 33]. AutoDockTool (ADT) [G. M. Morris,R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew, D. S. Goodsell, A. J.Olson, AutoDock4 and AutoDockTools4: Automated docking with selectivereceptor flexibility, J. Comput. Chem., 30 (2009) 2785-2791] was thenemployed to prepare the protein and compounds with partial charges andalso for the latter rotatable bonds. Only polar hydrogens were retainedin the molecules. Kollman united atom partial charges and solvationparameters were assigned. The search space of 44 Å×47 Å×41 Å wasslightly bigger than the protein molecule and the grid spacing was 0.375Å. Autogrid was run first to prepare the coordinates system and then aLamarckian genetic algorithm was applied with a population size of 150and 25 million maximum evaluations. The minimum empirical binding freeenergy (ΔG) between the compound and receptor was reported. The bindingaffinity K_(i) is calculated from binding free energy using the relationΔG=−RT ln(K_(i)), where R is the gas constant. All dockings wereperformed on an iMac computer with a 2.4 GHz Intel Core i3 processor and4 GB RAM.

To illustrate the useful biological activity of thesechroman-substituted and tetrahydroquinoline-substitutedheteroarotinoids, the compounds were screened against human A2480ovarian cancer cells. The data is presented in Tables 1 and 2.

It is clear from the data in Tables 1 and 2 that select groups on boththe A ring and the B ring are important for activity. The docking of thecompounds to mortalin was exploited to determine binding affinity andascertain if a correlation existed between docking and activity usingSHetA2 as the standard. Considering the efficacy values of thechroman-substituted agents as measures of activity, it is clear(Table 1) that the efficacy in 2a (Z═NO₂, Y═S), 3b (Z═CF₃, Y═O), 3c(Z═CN, Y═O), 3d (Z═OCF₃, Y═O), 6a (Z═NO₂, Y═S), 6b (Z═NO₂, Y═O), 6c(Z═CF₃, Y═O), 7a (Z═NO₂, Y═S), 7c (Z═NO₂, Y═O), 7d (Z═CF₃, Y═O), 8a(Z═NO₂, Y═S), and 8b (Z═NO₂, Y═O) exceeded the efficacy of SHetA2 (1),the standard. The IC₅₀ values, compared to that of SHetA2 (1), wereexceeded by those of 6a, 6b, 6c, 7c, 7d, 8b, 8c, and 8d. Overall, twoagents with the best IC₅₀ and efficacy values taken on the whole were 6b(Z═NO₂, Y═O; 2.17, 93.3%) and 7c (Z═NO₂, Y═O, 2.05, 93.6%) compared tothat of SHetA2 (Z═NO₂, Y═S, 3.17, 84.3%). An overall appraisal of thedata revealed that the urea derivatives were more active than thethiourea counterparts.

TABLE 1 Half-maximal inhibitory concentration and efficacy valuesderived from the cellular dose-response data for members of thechroman-containing series (X = O). Shown also are the standard errors ofmean (SEM) and binding free energy and binding affinity values ofcom-pounds docked to the mortalin substrate-binding domain (SBD) andcompared to SHetA2 (1). IC₅₀ IC₅₀ Efficacy Efficacy -ΔG K_(i) (μM) SEM(%) SEM (kcal/mol) (μM) SHetA2 3.17 ±0.05 84.3 ±0.7 8.5 0.6  2a 6.970.08 87 6 8.1 1.3  2b 4.3 3.0 26 10 8.0 1.5  2c 4.7 0.2 22 4 7.8 2.1  2e6.9 0.9 32 2 8.3 0.9 03a 4.1 0.1 79 4 8.5 0.6  3c 3.6 0.1 88.4 1.4 7.91.8  3d 4.7 0.3 93 3 8.6 0.5  3f 4.56 0.05 91.5 0.8 7.7 2.5  4a 6.4 0.619 5 7.8 2.1  4b 5.5 1.5 28 0.6 7.0 7.9  4c 4.3 0.4 16 6 7.3 4.8  5a 6.70.2 74 11 8.3 0.9  5b 5 0.3 47 2 7.8 2.1  5c 3.5 0.4 36 3 8.1 1.3  6a2.9 0.1 93.9 0.5 8.5 0.6  6b 2.17 0.04 93.2 0.1 8.3 0.9  6c 2.45 0.0492.4 0.1 8.1 1.3  7a 3.69 0.04 95.7 0.4 8.4 0.8  7b 4.7 0.5 11.8 0.9 8.21.1  7c 2.05 0.02 93.66 0.05 8.4 0.8  7d 2.43 0.05 93.3 0.1 8.6 0.5  8a4.6 0.2 94.00 1.00 8.7 0.5  8b 2.09 0.02 91.4 0.3 8.7 0.5  8c 2.0 0.186.2 0.6 8.8 0.4  8d 3.00 0.06 67 3 8.8 0.4

TABLE 2 Half-maximal inhibitory concentrations and efficacy values oftetrahydroquinoline-containing members (X = NH or N—CH₃). Data arederived from cellular dose-response data, and binding free energy andbinding affinity values of compounds docked to the mortalinsubstrate-binding domain (SBD) and compared to SHetA2 (1). See Scheme 9for the synthesis of compounds 9a-9d and 10; see Scheme 10 for thesynthesis of 11a-11g; see Scheme 11 for the synthesis of 12; and seeScheme 12 for the synthesis of 13a-f. -ΔG (kcal/ K_(i) Cpd Y Z IC₅₀ (μM)Efficacy (%) mol) (μM) SHetA2 S NO₂ 3.17 (±0.05) 84.3 (±0.7) 8.5 0.6  9aO NO₂  6.9 (0.2) 17.1 (±1.2) 8.2 1.1  9b S NO₂  7.1 (0.3) 17.8 (±1.6)7.9 1.6  9c S CF₃   6 (0.2)   42 (±3) 7.5 3.3  9d S OCF₃  7.1 (0.8)   24(±2) 7.2 5.4 10 O NO₂  6.6 (0.3)   22 (±4) 8.5 0.7 11a O NO₂  3.8 (0.1)94.8 (±2.2) 8.9 0.3 11b S NO₂  4.4 (0.2) 91.4 8.2 1.1 11c O CF₃ 2.58(0.08) 90.1 (±1.4) 8.0 1.5 11d S CF₃  3.9 (0.1) 90.8 (±2.0) 7.9 1.6 11eO OCF₃  2.4 (0.2) 91.3 (±1.3) 7.9 1.8 11f S OCF₃  5.4 (0.6)   76 (±8)7.7 2.4 11g S NH₂  7.7 (1.4)   24 (±4) 8.2 1.1 12 S NO₂ 4.49 (0.18) 91.7(±0.42) 8.7 0.5 13a O NO₂  8.4 (1.9)   26 (±4) 8.0 1.6 13b S NO₂   10(5)   25 (±4) 7.7 2.3 13c O CF₃  6.7 (0.5)   25 (±5) 8.4 0.7 13d O OCF₃ 7.6 (0.7) 56.1 (±2.4) 7.7 2.3 13e S CF₃  7.8 (0.2) 23.6 (±3.3) 8.2 1.113f S OCF₃ 13.1 (6.1) 15.3 (±3.3) 7.6 2.9

Series 14 compounds are those comprising a thiochroman group. Resultsfor this groups are shown in Table 3, where the standard of measurementwas SHetA2 which is the last component (X) in Table 3. It is noted thata range of activities was exhibited by the series 14 compounds, but 14a,14b, 14c, 14d, 14e, and 14f exceeded that of SHetA2 in efficacy as did14j, 14k, 14l, 14m, 14n, and 14o although the IC₅₀ values varied. Thedimethyl compound 14w also had an efficacy value better than SHetA2, butthe IC₅₀ was slightly less.

The compounds in Table 3 were designed to maintain the c log D valuesbetween 3 and 6 to avoid off-target liabilities arising due tointeractions with the Human Ether-a-go-go Related Gene (HERG),cytochrome P450 (CYP), and other transporting molecules.

TABLE 3 The data contain maximal inhibitory activity, binding affinity,and efficacy for the 14 series of compounds, as compared to SHetA2. Lrefers to the linking atoms between the thiochroman and the benzylmoiety; Ring B refers to the benzyl moiety (e.g. see Scheme 3). Cpd R LRing B clogD clog P IC₅₀ (μM) % Efficacy 14a CH₃ NHC(O)NH C₆H₄—4—CF₃6.17 6.2 3.79 ± 0.05 93.3 ± 0.1 14b CH₃ NHC(O)NH C₆H₄—4—OCF₃ 6.28 6.31.86 ± 0.09 95.6 ± 0.4 14c CH₃ NHC(O)NH C₆H₄—4—CN 5.26 5.3 3.93 ± 0.0393.3 ± 0.1 14d CH₃ NHC(S)NH C₆H₄—4—Cl 6.15 6.1 3.17 ± 0.25 91.9 ± 0.514e CH₃ NHC(S)NH C₆H₄—4—CF₃ 6.32 6.3 2.86 ± 0.29 95.9 ± 0.6 14f CH₃NHC(S)NH C₆H₄—4—OCF₃ 5.93 5.9 3.51 ± 0.07 95.3 ± 0.4 14g CH₃ NHC(S)NHC₆H₄—4—C(O)NH₂ 3.95 3.9 3.53 ± 0.12 64.2 ± 1.8 14h CH₃ NHC(S)NHC₆H₄—4—OCH₃ 5.45 5.4 2.78 ± 0.47 59.8 ± 1.2 14i CH₃ NHC(S)NH C₆H₄—3—OCH₃5.45 5.4 3.04 ± 0.52  38.8 ± 0.04 14j CH₃ NHC(S)NHCH₂ Ph 5.70 5.7 3.03 ±0.47 85.6 ± 0.6 14k CH₃ NHC(S)NHCH₂CH₂ Ph 6.34 6.3 3.19 ± 0.47 88.2 ±0.3 141 CH₃ NHC(S)NHCH₂ C₆H₄—4—Cl 6.45 6.4 2.98 ± 0.44 89.4 ± 2.8 14mCH₃ NHC(S)NHCH₂ C₆H₄—4—NO₂ 5.75 5.7 4.70 ± 0.11 94.5 ± 0.6 14n CH₃NHC(S)NHCH₂ C₆H₄—4—CF₃ 6.52 6.5 4.82 ± 0.41 95.3 ± 0.3 14o CH₃NHC(S)NHCH₂ C₆H₄—4—OCH₃ 5.64 5.6 3.26 ± 0.43 89.6 ± 0.9 14p CH₃NHC(S)NHCH₂ C₆H₄—4—OH 5.15 5.1 3.23 ± 0.49 56.8 ± 3.3 14q CH₃ NHC(S)NHNHPh 5.84 5.8 7.03 ± 0.31 63.6 ± 3.7 14r CH₃ NHC(S)NHNHC(O) Ph 4.08 4.00.82 ± 0.21 67.9 ± 2.6 14s CH₃ NHC(S)NHNHC(O) C₆H₄—4—NO₂ 3.85 3.8 3.15 ±0.19 43.3 ± 2.9 14t CH₃ NHC(S)NHNHC(O) C₆H₄—4—OCF₃ 4.97 4.9 3.60 ± 0.1857.4 ± 0.4 14u CH₃ NHC(S)NHNHC(O) C₆H₃—3,5—CF₃ 5.45 5.4  4.0 ± 0.12 61.4± 2.9 14v H NHC(S)NH Ph—4—NO₂ 3.36 3.3 4.01 ± 0.19 93.5 ± 1.7 14xCH₃NHC(S)NH Ph—4—NO₂ 5.15 5.1 3.17 ± 0.1  84.3 ± 0.7 NOTE: The lastentry (x) is the data for the standard [SHetA2] to which the testcompounds were compared.

Example 3. Synthesis Details and Analyses

This Example provides details of reactions leading to the compoundsdescribed herein and the analyses of the compounds. The compounds arekeyed according to compound number and the Scheme in which they aredepicted in EXAMPLE 1.

The following section pertains to Scheme 4, Scheme 5, Scheme 6, Scheme 7and Scheme 8

To obtain members of 2 and 3, the following general procedure wasemployed. A stirred solution of 1 mol eq of known6-amino-2,2,4,4-tetramethylchroman (21) in dry THF was treated at 0° C.with 1.05 mol eq of the appropriate isothiocyanate or isocyanate.Stirring was continued overnight with gradual warming to roomtemperature. The solvent was removed under vacuum to yield an oilyresidue. The residue was dissolved in chloroform and treated with asmall amount of pentane until crystallization commenced. In all cases,crystals obtained were filtered and washed with ether:pentane (1:1) toafford the products, which were dried (high vacuum) at 50° C.

1-(4-Nitrophenyl)-3-(2,2,4,4-tetramethylchroman-6-yl)thiourea (2a)

Pale yellow solid (160 mg, 85%), mp 176-177° C.; IR: 3307, 3190, 1542,1335 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J=9.1 Hz, 2H), 8.00 (brs, 1H), 7.76 (coincident s, 1H and d, J=9.1 Hz, 2H), 7.22 (d, J=2.6 Hz,1H), 7.04 (dd, J=8.5, 2.6 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 1.86 (s, 2H),1.38 (s, 6H), 1.36 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 180.5, 153.9,145.4, 144.9, 134.6, 128.4, 125.9, 125.8, 125.3, 123.6, 120.6, 75.8,48.7, 33.0, 31.4, 28.7. Anal. Calcd for C₂₀H₂₃N₃O₃S: C, 62.32; H, 6.01;N, 10.90. Found: C, 62.51; H, 6.05; N, 10.93. Although 2a was reportedand analyzed, the current purification procedure raised the mp by about10° C.

Ethyl 4-(3-(2,2,4,4-Tetramethylchroman-6-yl)thioureido)benzoate (2b)

White solid (70 mg, 70%), mp 140-141° C.; IR: 3349, 3284, 3195, 1709cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J=8.3 Hz, 2H), 7.91 (br s,1H), 7.72 (br s, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.24 (d, J=1.9 Hz, 1H),7.04 (dd, J=8.5, 1.9 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.36 (q, J=7.1 Hz,2H), 1.86 (s, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.37 (s, 6H), 1.35 (s, 6H);¹³C NMR (101 MHz, CDCl₃): δ 179.6, 165.9, 152.5, 142.0, 133.4, 130.5,128.2, 127.6, 125.0, 124.9, 123.0, 119.5, 75.2, 61.0, 48.5, 32.8, 31.1,28.5, 14.3. Anal. Calcd for C₂₃H₂₈N₂O₃S: C, 66.96; H, 6.84; N, 6.79.Found: C, 66.88; H, 6.85; N, 6.68.

1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea(2c)

White solid (82 mg, 81%), mp 166-168° C.; IR: 3357, 3196, 1598, 1491,1324 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.81 (br s, 1H), 7.63 (d, J=8.7Hz, 2H), 7.61 (br s, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.23 (d, J=2.6 Hz,1H), 7.04 (dd, J=8.6, 2.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 1.86 (s, 2H),1.38 (s, 6H), 1.35 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 179.9, 152.6,141.2, 133.6, 128.0, 128.6, 126.0 (q, J=3.9 Hz), 125.1, 125.0, 123.9,123.9 (q, J=271.9 Hz), 119.6, 75.7, 48.8, 33.0, 31.4, 28.7. Anal. Calcdfor C₂₁H₂₃F₃N₂OS: C, 61.75; H, 5.68; N, 6.86. Found: C, 61.47; H, 5.62;N, 6.87.

4-(3-(2,2,4,4-Tetramethylchroman-6-yl)thioureido)benzenesulfonamide (2d)

Tan solid (90 mg, 78%), mp 186-187° C.; IR: 3351, 3258, 3179, 1339, 1162cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.92 (s, 1H), 9.85 (s, 1H), 7.74 (d,J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.39 (s, 1H), 7.27 (s, 2H), 7.14(s, J=7.6 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 1.81 (s, 2H), 1.30 (2s, 12H);¹³C NMR (101 MHz, DMSO-d₆): δ 179.8, 149.9, 143.3, 139.3, 132.1, 131.4,126.5, 124.0, 123.5, 122.9, 117.6, 74.7, 48.5, 33.0, 31.1, 28.6. Anal.Calcd for C₂₀H₂₅N₃O₃S₂.0.5 CH₃CH₂OH: C, 56.99; H, 6.38; N, 9.49. Found:C, 56.67; H, 6.08; N, 9.87.

1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea(3a)

White solid (93 mg, 80%), mp 245-246° C.; IR: 3302, 3175, 1646, 1599,1491, 1325 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.51 (s,1H), 7.65 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.09(d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 1.80 (s, 2H), 1.30 (s, 6H),1.29 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ 151.9, 146.9, 143.1, 131.5,130.7, 125.4 (q, J=3.8 Hz), 124.0 (q, J=272.7 Hz), 120.9, 118.0, 117.1,117.0, 116.8, 73.3, 47.9, 32.0, 30.1, 27.6. Anal. Calcd forC₂₁H₂₃F₃N₂O₂.0.3 H₂O: C, 63.40; H, 5.98; N, 7.04. Found: C, 63.71; H,5.82; N, 7.12.

1-(4-Cyanophenyl)-3-(2,2,4,4-tetramethylchroman-6-yl)urea (3b)

Tan solid (51 mg, 61%), mp 225-226° C.; IR: 3341, 3206, 2221, 1665,1590, 1491 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.10 (s, 1H), 8.59 (s,1H), 7.71 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.43 (s, 1H), 7.10(d, J=7.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 1.80 (s, 2H), 1.29 (s, 12H);¹³C NMR (100 MHz, DMSO-d₆): δ 152.7, 148.1, 144.9, 133.7, 132.4, 131.8,119.8, 119.2, 118.4, 118.1, 117.9, 103.4, 74.4, 18.8, 33.0, 31.1, 28.6.Anal. Calcd for C₂₁H₂₃N₃O₂: C, 72.18; H, 6.63; N, 12.03. Found: C,72.00; H, 6.60; N, 11.76.

1-(2,2,4,4-Tetramethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea(3c)

White solid (151 mg, 76%), mp 219-221° C.; IR: 3313, 3206, 3154, 1646,1256 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.36 (d, J=8.1 Hz, 2H), 7.26(obscured by solvent, 1H), 7.13 (d, J=8.1 Hz, 2H), 6.97 (dd, J=8.2, 1.5Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.69 (s, 1H), 6.41 (s, 1H), 1.84 (s,2H), 1.36 (s, 6H), 1.34 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 153.2,147.8, 142.9, 139.7, 132.8, 131.7, 122.1, 120.7 (q, J=254.9 Hz), 119.7,119.0, 117.90, 117.85, 74.3, 48.9, 33.0, 31.1, 28.6. Anal. Calcd forC₂₁H₂₃F₃N₂O₃: C, 61.76; H, 5.68; N, 6.86. Found: C, 61.91; N, 5.59; N,6.85.

General Procedure for the Synthesis of Members of 4 and 5.

The procedures to obtain members of 4 and 5 were derived from the knownprecursor 4,4-dimethyl-3,4-dihydro-2H-1-benzopyran (23) in the normalsequence shown 16→22→23→24/25→26/27→4/5. An important step was thereduction of 24/25 to 26/27 using Fe/NH₄Cl in ethanol. The last stepinvolved the reaction of 26 with the corresponding isocyanate orisothiocyanate in THF under similar conditions as outlined for thegeneration of members of 2 and 3. Derivatives were obtained in similarfashion.

1-(4-Nitrophenyl)-3-(4,4-dimethylchroman-6-yl)thiourea (4a)

Compound 23 was converted to 4a using the general procedure describedabove. Yellow solid (118 mg, 79%), mp 174-165° C.; IR: 3305, 3187, 1596,1528, 1495, 1335 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J=8.8 Hz,2H), 7.97 (br s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.21 (d,J=2.2 Hz, 1H), 7.03 (dd, J=8.4, 2.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H),4.24 (t, J=5.3 Hz, 2H), 1.87 (t, J=5.3 Hz, 2H), 1.35 (s, 6H); ¹³C NMR(101 MHz, CDCl₃): δ 179.4, 153.9, 144.5, 144.0, 133.9, 127.4, 125.2,125.1, 124.5, 122.8, 118.9, 63.3, 36.9, 30.94, 30.89. Anal. Calcd forC₁₈H₁₉N₃O₃S: C, 60.49; H, 5.36; N, 11.76. Found: C, 60.44; H, 5.35; N,11.74.

1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (4b)

White solid (160 mg, 75%), mp 147-149° C.; IR: 3357, 3199, 1613, 1498,1324 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (br s, 1H), 7.68 (br s, 1H),7.65 (d, J=8.9 Hz, 2H), 7.61 (d, J=8.9 Hz, 2H), 7.22 (s, 1H), 7.03 (d,J=8.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 4.22 (t, J=5.4 Hz, 2H), 1.85 (t,J=5.4 Hz, 2H), 1.34 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 179.9, 153.6,141.5, 133.6, 127.9, 126.1 (q, J=3.8 Hz), 125.2, 125.1, 123.9, 123.9 (q,J=271.9 Hz), 118.6, 63.2, 36.9, 30.94, 30.86 (1 aromatic carbon notresolved). Anal. Calcd for C₁₉H₁₉F₃N₂OS: C, 59.99; H, 5.03; N, 7.36.Found: C, 60.04; H, 5.09; N, 7.37.

1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea (4c)

White solid (172 mg, 90%), mp 153-154° C.; IR: 3358, 3189, 1530, 1500,1255 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.71 (br s, 1H), 7.48 (coincidentd, J=9.0 Hz, 2H and br s, 1H), 7.26 (s, 1H), 7.21 (d, J=9.0 Hz, 2H),7.01 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.22 (t, J=5.3 Hz, 2H),1.85 (t, J=5.3 Hz, 2H), 1.34 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 181.6,154.5, 147.9, 137.3, 134.3, 128.8, 127.0, 126.1, 126.0, 122.8, 121.1 (q,J=257.1 Hz), 119.3, 63.7, 37.2, 31.13, 31.05. Anal. Calcd forC₁₉H₁₉F₃N₂O₂S: C, 57.57; H, 4.83; N, 7.07. Found: C, 57.54; H, 4.76; N,7.19.

1-(4-Nitrophenyl)-3-(4,4-dimethylchroman-6-yl)urea (5a)

Compound 23 was converted to 5a using the general procedure describedabove. White solid (94 mg, 80%), mp 240-242° C.; IR: 3281, 3189, 1640,1556, 1333 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.64 (s,1H), 8.18 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.42 (d, J=2.2 Hz,1H), 7.10 (d, J=8.9 Hz, 1H), 6.67 (d, J=8.8, 2.2 Hz, 1H), 4.11 (t, J=5.2Hz, 2H), 1.78 (d, J=5.2 Hz, 2H), 1.28 (s, 6H); ¹³C NMR (101 MHz,DMSO-d₆): δ 152.6, 149.4, 147.1, 141.2, 132.03, 132, 02, 125.6, 119.2,118.3, 117.8, 117.0, 62.8, 37.5, 31.3, 30.8. Anal. Calcd for C₁₈H₁₉N₃O₄:C, 63.33; H, 5.61; N, 12.31. Found: C, 63.07; H, 5.64; N, 12.50.

(4,4-Dimethylchroman-6-yl)-3-[4-trifluoromethyl)phenyl]urea (5b)

White solid 5b (84 mg, 82%), mp 248-249° C.; IR: 3301, 3186, 1645, 1320cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.52 (s, 1H), 7.65 (d,J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.41 (d, J=2.6 Hz, 1H), 7.11 (dd,J=8.8, 2.6 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 4.10 (t, J=5.2 Hz, 2H), 1.77(t, J=5.2 Hz, 2H), 1.28 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ 152.9,149.2, 144.1, 132.3, 132.0, 127.1 (q, J=3.6 Hz), 124.4 (q, J=270.0 Hz),124.3, 119.7, 118.7, 118.6, 117.6, 62.7, 37.5, 31.3, 30.8. Anal. Calcdfor C₁₉H₁₉F₃N₂O₂: C, 62.63; H, 5.26; N, 7.69. Found: C, 62.56; H, 5.32;N, 7.65.

1-(4,4-Dimethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea (5c)

White solid (78 mg, 73%), mp 230-231° C.: IR: 3308, 3198, 1645, 1267cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.52 (s, 1H), 7.65 (d,J=8.9 Hz, 2H), 7.61 (d, J=8.9 Hz, 2H), 7.41 (d, J=1.9 Hz, 1H), 7.09 (dd,J=8.7, 1.9 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.10 (t, J=5.2 Hz, 2H), 1.77(t, J=5.2 Hz, 2H), 1.28 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ 152.2,147.9, 142.3, 138.8, 131.1, 130.5, 121.8, 120.3 (q, J=255.4 Hz), 119.4,118.6, 117.6, 116.6, 61.7, 36.5, 30.1, 29.7. Anal. Calcd forC₁₉H₁₉F₃N₂O₃: C, 60.00; H, 5.04; N, 7.36. Found 60.06; 5.20; 7.33.

General Procedure for the Preparation of Members of 6, 7, and 8.

The methodology for obtaining members of 6, 7, and 8 paralleled to somedegree that employed for the procurement of members of 4 and 5. Startingfrom known 4,4-dimethylchroman-2-one (16), a small excess ofethylmagnesium bromide in ether was added directly to yield2-(4-ethyl-4-hydroxy-2-methylhexan-2-yl)phenol (28). The use of 28 andthe intermediates 29→30/31→32/33→6 led to good yields of 6a, 6b, and 6c.Both precursors 30 and 31 could not be separated, but it was possible toseparate amines 32 and 33. Only the 6-isomer 32 was employed to derivemembers of 6. The preparation of each other intermediate followed.Starting from phenol, the sequence of steps included34→35→36→37→38/39→40/41→40→7 and produced members of 7 in good yieldsvia the usual treatment of 40 with the required isocyanate orisothiocyanate. None of the intermediates were previously known and weretherefore characterized. Thus, all members of 7 were subjected to IR,NMR, and elemental analysis along with a determination of their sharpmelting points.

In a similar manner, members of 8 were prepared utilizing the startingcompound 35. An excess of ethylmagnesium bromide in ether opened thering in 35 to initiate the reaction sequence to produce members of 8 via35→42→43→44/45→46?8. It was possible to separate 44/45 by preparativethin layer chromatography to give pure 44 (C-6 isomer). Reduction of thenitro group in 44 to the amino group yielded the required 46 (C-6isomer) which was converted via reaction with the appropriate isocyanateor isothiocyanate to provide 8. Intermediates were oils which werepurified by chromatography. All members of 8 were solids, had sharpmelting points, and were characterized by IR, NMR, and elementalanalyses.

1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-nitrophenyl)thiourea (6a)

Compound 32 was converted to 6a using the appropriate isocyanate orisothiocyanate in the usual manner. Yellow solid (160 mg, 90%), mp175-176° C.; IR: 3341, 3174, 1556, 1340, 1174 cm⁻¹; ¹H NMR (400 MHz,DMSO-d₆): δ 10.2 (s, 1H), 10.1 (s, 1H), 8.18 (d, J=9.0 Hz, 2H), 7.80 (d,J=9.0 Hz, 2H), 7.38 (d, J=2.7 Hz, 1H), 7.14 (dd, J=8.6, 2.7 Hz, 1H),6.71 (d, J=8.6 Hz, 1H), 1.77 (s, 2H), 1.68-1.46 (complex, 4H), 1.28 (s,6H), 0.85 (t, J=7.4 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ 179.5, 150.0,146.8, 142.5, 132.2, 131.9, 124.8, 123.8, 123.2, 121.8, 117.8, 79.1,44.2, 33.2, 30.7, 29.1, 8.1. Anal. Calcd for C₂₂H₂₇N₃O₃S: C, 63.90; H,6.58; N, 10.16. Found: C, 64.07; H, 6.64; N, 10.11.

1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-nitrophenyl)urea (6b)

Compound 32 was converted to 6b using the general procedure describedabove. Yellow solid (145 mg, 85%), mp 190-192° C.; IR: 3333, 1662, 1556,1331 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.33 (s, 1H), 8.64 (s, 1H), 8.18(d, J=8.9 Hz, 2H), 7.69 (d, J=8.9 Hz, 2H), 7.43 (d, J=2.7 Hz, 1H), 7.11(dd, J=8.6, 2.7 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 1.76 (s, 2H), 1.61 (m,2H), 1.52 (m, 2H), 1.29 (s, 6H), 0.84 (t, J=7.4 Hz, 6H); ¹³C NMR (101MHz, DMSO-d₆): δ 152.6, 148.1, 147.1, 141.2, 132.6, 132.3, 125.6, 119.2,118.4, 118.0, 117.8, 78.8, 44.6, 33.1, 30.8, 29.1, 8.1. Anal. Calcd forC₂₂H₂₇N₃O₄.0.15 H₂O: C, 66.03; H, 6.88; N, 10.53. Found: C, 65.64; H,6.68; N, 10.91.

1-(2,2-Diethyl-4,4-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea(6c)

White solid (166 mg, 92%), mp 208-210° C.; IR: 3326, 3202, 3142, 1659,1323 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 8.35 (s, 1H), 7.62(d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.39 (s, 1H), 7.07 (d, J=8.6Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 1.77 (s, 2H), 1.65 (m, 2H), 1.54 (m,2H), 1.32 (s, 6H), 0.87 (t, J=7.3 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ153.0, 148.1, 143.9, 132.5, 132.3, 126 (q, J=3.6 Hz), 124.6 (q, J=269.8Hz), 122.5, 122.2, 118.7, 117.7, 117.6, 78.3, 44.0, 32.2, 30.0, 28.2,7.1. Anal. Calcd for C₂₃H₂₇F₃N₂O₂: C, 65.70; H, 6.47; N, 6.66. Found: C,65.94; H, 6.51; N, 6.67.

1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-nitrophenyl)thiourea (7a)

Compound 40 was converted to 7a using the general procedure describedabove. Yellow solid (155 mg, 87%), mp 174-175° C.; IR: 3344, 3183, 3115,1546, 1333, 1257 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 10.2 (s, 1H), 10.1(s, 1H), 8.19 (d, J=9.0 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.30 (d, J=2.5Hz, 1H), 7.12 (dd, J=8.6, 2.5 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 1.75 (s,2H), 1.70-1.54 (complex, 4H), 1.29 (s, 6H), 0.71 (t, J=7.3 Hz, 6H); ¹³CNMR (101 MHz, DMSO-d₆): δ 179.3, 151.6, 146.9, 142.5, 131.9, 130.1,124.9, 123.8, 123.5, 121.6, 117.7, 74.7, 40.3, 37.6, 33.5, 29.1, 8.8.Anal. Calcd for C₂₂H₂₇N₃O₃S₃: C, 63.90; H, 6.58; N, 10.16. Found: C,63.63; H, 6.53; N, 10.06.

1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea(7b)

White solid (159 mg, 85%), mp 155-156° C.; IR: 3360, 3154, 1302, 1162cm⁻¹; NMR (400 MHz, DMSO-d₆): δ 9.95 (s, 1H), 9.87 (s, 1H), 7.72 (d,J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 7.10 (dd,J=8.5, 2.5 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 1.75 (s, 2H), 1.61 (m, 4H),1.29 (s, 6H), 0.72 (t, J=7.2 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ179.9, 151.4, 143.9, 132.1, 130.0, 126.0 (q, J=3.4 Hz), 124.9 (q,J=271.2 Hz), 124.2, 123.8, 123.6, 122.9, 117.6, 74.6, 37.5, 33.5, 29.1,8.8 (one aliphatic carbon obscured by solvent). Anal. Calcd forC₂₃H₂₇F₃N₂OS: C, 63.28; H, 6.23; N, 6.42. Found: C, 63.38; H, 6.21; N,6.40.

1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-nitrophenyl)urea (7c)

Compound 33 was converted to 7c using the general procedure describedabove. Yellow solid (150 mg, 88%), mp 228-229° C.; IR: 3292, 3154, 3098,1652, 1559, 1332 cm⁻¹; NMR (400 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.67 (s,1H), 8.18 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.37 (d, J=2.5 Hz,1H), 7.09 (dd, J=8.6, 2.5 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 1.74 (s, 2H),1.72-1.55 (complex, 4H), 1.28 (s, 6H), 0.73 (t, J=7.3 Hz, 6H); ¹³C NMR(101 MHz, DMSO-d₆) δ 152.5, 149.7, 147.1, 141.2, 132.2, 130.4, 125.6,118.8, 118.3, 117.9, 117.8, 74.3, 40.1, 37.6, 33.6, 29.0, 8.8. Anal.Calcd for C₂₂H₂₇N₃O₄: C, 66.48; H, 6.85; N, 10.57. Found: C, 66.22; H,6.86; N, 10.37.

1-(4,4-Diethyl-2,2-dimethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea(7d)

White solid (164 mg, 91%), mp 225-226° C.; IR: 3312, 3169, 1652, 1554,1328 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.54 (s, 1H), 7.65(d, J=8.9 Hz, 2H), 7.61 (d, J=8.9 Hz, 2H), 7.35 (d, J=2.7 Hz, 1H), 7/08(dd, J=8.6, 2.7 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 1.74 (s, 2H), 1.68-1.54(complex, 4H), 1.27 (s, 6H), 0.73 (t, J=7.3 Hz, 6H); ¹³C NMR (101 MHz,DMSO-d₆): δ 152.9, 149.4, 144.2, 132.5, 130.3, 126.5 (q, J=4.0 Hz),125.1 (q, J=270.0 Hz), 122.0, 121.7, 118.6, 118.1, 117.8, 74.3, 37.6,33.6, 29.0, 8.8 (one aliphatic carbon obscured by solvent). Anal. Calcdfor C₂₃H₂₇F₃N₂O₂: C, 65.70; H, 6.47; N, 6.66. Found: C, 65.55; H, 6.44;N, 6.61.

1-(4-Nitrophenyl)-3-(2,2,4,4-tetraethylchroman-6-yl)thiourea (8a)

Compound 46 was converted to 8a using the general procedure describedabove. Light yellow solid (162 mg, 85%), mp 162-164° C. IR: 3339, 3178,1512, 1336 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J=8.8 Hz, 2H), 8.05(br s, 1H), 7.75 (coincident d, J=8.9 Hz, 2H and br s, 1H), 7.11 (d,J=2.1 Hz, 1H), 7.03 (dd, J=8.4, 2.1 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),1.78 (s, 2H), 1.78-1.55 (complex, 8H), 0.91 (t, J=7.4 Hz, 6H), 0.77 (t,J=7.3 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 179.4, 154.6, 144.4, 144.0,133.4, 127.3, 125.2, 124.9, 124.5, 122.6, 119.8, 80.0, 37.6, 36.2, 33.4,29.9, 8.5, 7.8. Anal. Calcd for C₂₄H₃₁N₃O₃S.0.2H₂O: C, 64.75; H, 7.11;N, 9.44. Found: C, 64.75; H, 7.12; N, 9.36.

1-(4-Nitrophenyl)-3-(2,2,4,4-tetraethylchroman-6-yl)urea (8b)

Compound 46 was converted to 8b using the general procedure describedabove. Light yellow solid (148 mg, 91%), mp 163-164° C.; IR: 3342, 3220,3158, 3098, 1662, 1512, 1336 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.34 (s,1H), 8.67 (s, 1H), 8.18, J=9.1 Hz, 2H), 7.69 (d, J=9.1 Hz, 2H), 7.36 (d,J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.5 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H),1.70 (s, 2H), 1.72-1.43 (complex, 8H), 0.83 (t, J=7.3 Hz, 6H), 0.73 (t,J=7.3 Hz, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ 152.5, 149.6, 147.1, 141.2,132.3, 131.3, 125.6, 118.7, 118.2, 118.0, 117.7, 78.8, 37.5, 36.9, 33.5,29.6, 8.7, 8.0. Anal. Calcd for C₂₄H₃₁N₃O₄: C, 67.74; H, 7.34; N, 9.88.Found: C, 67.59; H, 7.35; N, 9.83.

1-(2,2,4,4-Tetraethylchroman-6-yl)-3-(4-(trifluoromethyl)phenyl)urea(8c)

White solid (176 mg, 91%), mp 165-166° C.; IR: 3309, 3203, 3142, 3095,1655, 1327 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.54 (s,1H), 7.65 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.34 (d, J=1.3 Hz,1H), 7.08 (dd, J=8.6, 1.3 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 1.70 (s, 2H),1.70-1.43 (complex, 8H), 0.83 (t, J=7.3 Hz, 6H), 0.72 (t, J=7.3 Hz, 6H);¹³C NMR (101 MHz, DMSO-d₆): δ 151.9, 148.3, 143.1, 131.5, 130.2, 125.4(q, J=3.5 Hz), 124.8 (q, J=270.9 Hz), 120.7 (q, J=31.9 Hz), 117.5,117.1, 117.0, 116.9, 77.7, 36.4, 36.0, 32.5, 28.6, 7.7, 7.0. Anal. Calcdfor C₂₅H₃₁F₃N₂O₂: C, 66.95; H, 6.97; N, 6.25. Found: C, 66.94; H, 6.98;N, 6.18.

1-(2,2,4,4-Tetraethylchroman-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea(8d)

White solid (156 mg, 78%), mp 180-181° C.; IR: 3295, 3201, 1645, 1267cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.46 (s, 1H), 7.55 (d,J=8.9 Hz, 2H), 7.32 (d, J=2.5 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.08 (dd,J=8.6, 2.5 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 1.70 (s, 2H), 1.70-1.43(complex, 8H), 0.83 (t, J=7.4 Hz, 6H), 0.72 (t, J=7.3 Hz, 6H); ¹³C NMR(101 MHz, DMSO-d₆): δ 151.2, 148.2, 141.8, 138.7, 131.8, 130.2, 121.1,119.6 (q, J=255.1 Hz), 118.6, 117.3, 116.83, 116.82, 77.6, 36.4, 35.9,32.5, 28.6, 7.7, 7.0. Anal. Calcd for C₂₅H₃₁F₃N₂O₃: C, 64.64; H, 6.73;N, 6.03. Found: C, 64.38; H, 6.66; N, 5.98.

The following analyses pertain to compounds Scheme 9, Scheme 10, Scheme11 and Scheme 12.

General Procedure for the Preparation of 9 and 10.

Members of 9 and 10 utilized 4-bromoaniline (47) as the startingmaterial followed by the individual steps shown. The sequence of47→48→49→50→51→52→53→54→9→10 are not known by prior art, and exactconditions for each step herein were critical to obtain each newcompound in pure form. To a stirred solution of 53 (0.2 g, 0.7 mmol) inTHF (5 mL) was added various iso(thio)cyanates (0.7 mmol) in THF (2 mL)dropwise at room temperature. The mixture was stirred until the TLCanalysis indicated that 53 was completely consumed. The solvent wasevaporated under vacuum to give the Boc-protected urea and (thio)ureaderivatives 54a-d. To the resulting Boc-protected compound indichloromethane (DCM, 5 mL) was slowly added trifluoroacetic acid (200μL, 2.6 mmol), and the mixture was stirred until TLC indicated theabsence of 9a-d. The solvent was removed under vacuum. Two additionalportions of DCM (2×10 mL) were added and removed under vacuum. Water (20mL) was added to the resulting residue, and the mixture was washed withether (2×20 mL). The aqueous layer was basified using NaHCO₃ powder andextracted with EtOAc (3×20 mL). Combined organic extracts were washedwith water (2×20 mL), saturated NaCl (20 mL), dried (MgSO₄), filteredand concentrated under vacuum. Recrystallization of the products frompentane/ether (3:7) afforded pure 9a-d. All members of 9 were solidswith sharp melting points and gave the expected structural data from IR,NMR, and elemental analyses. Compound 9 was N-methylated to give salt10.

1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)urea(9a)

Yield: 153 mg (0.45 mmol, 64%) as a yellow solid, mp 219-220° C.; IR(nujol): 1698, 1548, 1180, 851 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.23(s, 1H), 8.36 (s, 1H), 8.16 (d, J=8.9 Hz, 2H), 7.66 (d, J=8.9 Hz, 2H),7.18 (s, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.39 (d, J=8.5 Hz, 1H), 5.54 (s,1H), 3.16 (s, 2H), 1.61 (s, 2H), 1.22 (s, 6H); ¹³C NMR (101 MHz,DMSO-d₆): δ 152.6, 147.4, 141.0, 129.4, 127.6, 125.6 (2C), 119.5, 118.7,117.6, 114.1, 37.8, 37.3, 31.9, 31.3. Anal. Calcd. for C₁₈H₂₀N₄O₃: C,63.52; H, 5.92; N, 16.46. Found: C, 63.36; H, 6.08; N, 16.51.

1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)thiourea(9b)

Yield: 164 mg (0.46 mmol, 66%) as a red solid, mp 150-152° C.; IR(nujol): 3333, 1509, 1334, 1263 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.19(d, J=8.6 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.71 (obscured signal, 2H),7.09 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.50 (d, J=8.3 Hz, 1H), 4.19 (brs, 1H), 3.39-3.36 (m, 2H), 1.76-1.74 (m, 2H), 1.30 (s, 6H); ¹³C NMR (101MHz, CDCl₃): δ 179.5, 144.28, 144.25, 144.1, 131.6, 125.1, 124.8, 124.4,123.3, 122.7, 114.9, 38.2, 36.2, 32.0, 30.6: Anal. Calcd. forC₁₈H₂₀N₄O₂S: C, 60.65; H, 5.65; N, 15.72. Found: C, 60.53; H, 5.82; N,15.87.

1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea(9c)

Yield: 169 mg (0.44 mmol, 63%) as a yellow solid, mp 104-105° C.; IR(nujol): 3346, 1512, 1324 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.67 (br s,1H), 7.65 (d, J=8.9 Hz, 2H), 7.58 (d, J=8.9 Hz, 2H and s, 1H), 7.11 (d,J=2.4 Hz, 1H), 6.89 (dd, J=8.4, 2.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H),4.02 (br s, 1H), 3.36 (t, J=5.9 Hz, 2H), 1.75 (t, J=5.9 Hz, 2H), 1.29(s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 180.1, 143.9, 141.4, 131.5, 127.4(q, J=32.9 Hz), 125.9 (br), 125.2, 124.9, 123.9 (q, J=271.5 Hz), 123.8,114.8, 38.9, 36.3, 32.0, 30.6 (1 aromatic C unresolved). Anal. Calcd.for C₁₉H₂₀F₃N₃S: C, 60.14; H, 5.31; N, 11.07. Found: C, 60.28; H, 5.12;N, 11.28.

1-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea(9d)

Yield: 164 mg (0.42 mmol, 60%) as a yellow solid, mp 69-71° C.; IR(nujol): 3348, 3186, 1509, 1257 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.69(br s, 1H), 7.49 (d, J=9.0 Hz, 2H and s, 1H), 7.18 (d, J=9.0 Hz, 2H),7.11 (d, J=2.4 Hz, 1H), 6.89 (dd, J=8.0, 2.4 Hz, 1H), 6.48 (d, J=8.0 Hz,1H), 4.20 (br s, 1H), 3.35 (t, J=5.5 Hz, 2H), 1.74 (t, J=5.5 Hz, 2H),1.29 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 180.4, 146.7, 143.8, 136.8,131.4, 126.1, 125.2, 124.9, 124.0 (br), 121.3, 120.4 (q, J=257.4 Hz),114.8, 38.2, 36.3, 31.9, 30.7. Anal. Calcd. for C₁₉H₂₀F₃N₃OS: C, 57.71;H, 5.10; N, 10.63. Found: C, 57.56; H, 5.23; N, 10.37.

1,1,4,4-Tetramethyl-6-(3-(4-nitrophenyl)ureido)-1,2,3,4-tetrahydroquinolin-1-iumIodide (10)

To a stirred solution of 9a (0.2 g, 0.6 mmol) in DMF (5 mL) in a 15 mLChemglass pressure vessel (No. CG-1880-01) was added Cs₂CO₃ (390 mg, 1.2mmol) and methyl iodide (1.0 mL, 16.0 mmol). The vessel was closed, andthe reaction was stirred at room temperature for 24 h. Water (5 mL) wasadded and the solid was filtered. The crude solid was stirred withethanol (10 mL) for 15 min and filtered to provide 10 as a yellow solid(185 mg, 0.37 mmol, 62%), mp 249-251° C.; IR: 3297, 3260, 1724, 1598,843 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 9.59 (s, 1H), 9.21 (s, 1H), 8.21(d, J=8.9 Hz, 2H), 7.88 (d, J=9.2 Hz, 1H), 7.71 (d, J=8.9 Hz, 2H), 7.67(s, 1H), 7.51 (d, J=9.2 Hz, 1H), 3.89 (m, 2H), 3.56 (s, 6H), 2.11 (m,2H), 1.36 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 151.4, 145.4, 140.7,139.7, 139.4, 135.0, 124.5, 121.3, 117.4, 117.2, 116.7, 59.4, 56.1,31.6, 30.5, 26.8: Anal. Calcd. for C₂₀H₂₅IN₄O₃: C, 48.40; H, 5.08; N,11.29. Found: C, 48.65; H, 5.23; N, 11.52.

General Procedure for the Preparation of Members of 11.

An entry to members of 11 is delineated in Scheme 10. A modified Skraupreaction on 4-bromoaniline with acetone and bismuth(III)trifluoromethanesulfonate gave the dihydroquinoline 55 (62%). A solutionof 55 in DMF was carefully treated with a 4-fold excess of methyl iodidein DMF at 15° C. and was allowed to warm slowly to room temperature.Stirring for an additional 18 hours generated 56 (82%). Alcohol 57 (57%)was realized by hydroboration of the double bond in 56. Oxidation 57 viaa Swern procedure led to the tetrahydroquinolinone 58, which wasimmediately alkylated to 59 (62%). Utilizing a pressure vessel, amixture of 59, copper(I) iodide, L-proline, DMF and aq. ammonia washeated to produce aniline 60 (65%). A series of isocyanates andisothiocyanates were added to 60, leading to solid derivatives 11(60-78%) which were purified by chromatography and crystallized fromether:pentane (3:7). All members of 11 gave the correct IR, NMR, andelemental analyses.

1-(4-Nitrophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea(11a)

Yield: 0.25 g (0.64 mmol, 74%) as an orange solid, mp 200-201° C.; IR(nujol): 1718, 1655, 1556 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (s,1H), 8.73 (s, 1H), 8.18 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.35(s, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 2.79 (s, 3H),1.39 (s, 6H), 1.20 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ 213.6, 151.5,146.0, 140.4, 140.2, 131.1, 129.6, 124.5, 118.2, 116.7, 115.4, 113.7,63.1, 46.5, 30.2, 22.2, 22.1. Anal. Calcd. for C₂₁H₂₄N₄O₄: C, 63.62; H,6.10; N, 14.13. Found: C, 63.39; H, 6.26; N, 14.27.

1-(4-Nitrophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiourea(11b)

Yield: 0.23 g (0.56 mmol, 65%) as a yellow solid, mp 145-147° C.; IR(nujol): 3308, 1715, 1532, 1498, 1332 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ8.20 (d, J=8.7 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.69 (s,1H), 7.21 (dd, J=8.6, 2.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.88 (d,J=8.5 Hz, 1H), 2.91 (s, 3H), 1.45 (s, 6H), 1.32 (s, 6H); ¹³C NMR (101MHz, CDCl₃): δ 213.6, 179.4, 145.7, 144.5, 144.0, 132.7, 127.0, 125.7,124.5, 123.0, 122.8, 115.1, 64.4, 47.7, 31.1, 23.7, 23.0. Anal. Calcd.for C₂₁H₂₄N₄O₃S: C, 61.15; H, 5.86; N, 13.58. Found: C, 61.38; H, 5.52;N, 13.37.

1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea(11c)

Yield: 0.28 g (0.67 mmol, 78%) as a brown solid, mp 198-199° C.; IR(nujol): 3328, 1720, 1656 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (s,1H), 8.52 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.32-7.24 (complex, 4H), 6.79(d, J=8.6 Hz, 1H), 2.82 (s, 3H), 1.38 (s, 6H), 1.19 (s, 6H); ¹³C NMR(CDCl₃): δ 213.7, 151.8, 143.1, 140.1, 131.4, 129.6, 125.4 (q, J=3.5Hz), 124.1 (q, J=272.5 Hz), 120.8 (q, J=32.0 Hz), 118.1, 117.1, 115.3,113.7, 63.1, 46.5, 30.2, 22.2. Anal. Calcd. for C₂₂H₂₄F₃N₃O₂: C, 63.00;H, 5.77; N, 10.02. Found: C, 63.12; H, 5.59; N, 10.29.

1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-trifluoromethyl)phenyl)thiourea(11d)

Yield: 0.25 g (0.58 mmol, 67%) as a brown solid, mp 149-151° C.; IR(nujol): 3291, 3206, 1716, 1615, 1324 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ7.88 (s, 1H), 7.65 (s, 1H), 7.61 (d, J=9.1 Hz, 2H), 7.59 (d, J=9.1 Hz,2H), 7.22 (dd, J=8.5, 2.6 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.86 (d,J=8.5 Hz, 1H), 2.90 (s, 3H), 1.48 (s, 6H), 1.32 (s, 6H); ¹³C NMR (101MHz, CDCl₃): δ 214.0, 179.8, 145.3, 141.1, 132.3, 127.8 (q, J=32.6 Hz),127.7 (br), 126.1 (q, J=2.7 Hz), 125.6, 124.1, 123.9 (q, J=272.0 Hz),122.7, 115.0, 64.4, 47.6, 31.1, 23.6, 23.0. Anal. Calcd. forC₂₂H₂₄F₃N₃OS: C, 60.67; H, 5.55; N, 13.09. Found: C, 60.94; H, 5.23; N,13.28.

1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea(11e)

Yield: 0.27 g (0.62 mmol, 72%) as a brown solid, mp 191-192° C.; IR(nujol): 3318, 1716, 1648 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.01 (s,1H), 8.61 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.32(d, J=2.4 Hz, 1H), 7.30 (dd, J=8.5, 2.4 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H),2.79 (s, 3H), 1.39 (s, 6H), 1.19 (s, 6H); ¹³C NMR (101 MHz, DMSO-d₆): δ213.7, 152.1, 141.8, 140.0, 138.7, 131.6, 129.6, 121.1, 119.6 (q,J=255.2 Hz), 118.6, 117.9, 115.2, 113.7, 63.1, 46.5, 30.2, 22.1. Anal.Calcd. for C₂₂H₂₄F₃N₃O₃: C, 60.68; H, 5.56; N, 9.65. Found: C, 60.79; H,5.76; N, 9.83.

1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea(11f)

Yield: 0.24 g (0.52 mmol, 60%) as a brown solid; mp 83-85° C.; IR(nujol): 3291, 3213, 1716, 1501 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.76(s, 1H), 9.72 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.30 (coincident d, J=8.8Hz, 2H and dd, J=8.7, 2.1 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 6.83 (d,J=8.7 Hz, 1H), 2.81 (s, 3H), 1.37 (s, 6H), 1.21 (s, 6H); ¹³C NMR (101MHz, DMSO-d₆): δ 213.5, 178.9, 143.8, 142.0, 138.3, 130.8, 129.1, 124.6,123.3, 120.5, 120.2, 119.5 (q, J=255.7 Hz), 113.3, 63.2, 46.4, 30.3,22.4, 22.1. Anal. Calcd. for C₂₂H₂₄F₃N₃O₂S: C, 58.52; H, 5.36; N, 9.31.Found: C, 58.29; H, 5.12; N, 9.07.

1-(4-Aminophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl)urea(11g)

To a stirred suspension of 11a (120 mg, 0.30 mmol) and iron powder (106mg, 1.88 mmol) in ethanol:water (4:1, 6.0 mL) was added NH₄Cl (48 mg,0.90 mmol), and the resulting mixture was refluxed for 12 h. Thereaction was cooled and filtered through CELITE®. The CELITE was washedwith ethanol (3×5 mL) and the filtrate was concentrated under vacuum at45° C. to give a brown solid. Recrystallization of the solid fromether-pentane gave pure 11g (92 mg (0.25 mmol, 84%) as a brown solid, mp135-137° C.; IR (nujol): 3297, 1713, 1642, 1601, 1502 cm⁻¹; ¹H NMR (400MHz, DMSO-d₆): δ 8.26 (s, 1H), 8.00 (s, 1H), 7.38-7.22 (complex, 2H),7.05 (d, J=8.2 Hz, 2H), 6.76 (d, J=8.6 Hz, 1H), 6.50 (d, J=8.2 Hz, 2H),4.76 (br s, 2H), 2.77 (s, 3H), 1.37 (s, 6H), 1.18 (s, 6H); ¹³C NMR (101MHz, DMSO-d₆): δ 213.8, 152.6, 143.2, 139.5, 132.4, 129.5, 128.2, 120.0,117.4, 114.7, 113.7, 113.5, 63.1, 46.5, 30.2, 22.2, 22.1. Anal. Calcd.for C₂₁H₂₆N₄O₂: C, 68.83; H, 7.15; N, 15.29. Found: C, 68.66; H, 7.26;N, 15.07.

General Procedure for the Preparation of 12 (Scheme 11).

The reaction pathway and intermediates leading to 69 are reasonable tothose versed in the art of synthesis, although the reaction conditionsfor the conversions are crucial. The general procedure to obtain membersof 12 are as follows. To a stirred solution of 69 (0.11 g, 0.50 mmol) inTHF (5 mL) was added dropwise two isothiocyanates (0.86 mmol) in THF (2mL) at room temperature under a nitrogen atmosphere. The reaction wasstirred until TLC analysis indicated the complete consumption of 69. Thesolvent was evaporated under vacuum, the residue was purified by columnchromatography (20-40% ether in hexanes gradient), and the product wascrystallized from ether in pentane (3:7) to afford 12. Both isomers weresolids and gave the correct IR, NMR, and elemental analyses.

3-(1,2,2,4,4-Pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-(4-nitrophenyl)thiourea(12)

Yield: 0.18 g, (0.45 mmol, 90%) as an orange solid, mp 151-153° C.; IR:3335, 1596, 1500, 1332, 1263, 851 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.17(d, J=9.3 Hz, 2H), 7.97 (s, 1H), 7.78 (d, J=8.8 Hz, 2H and s, 1H), 7.08(d, J=2.2 Hz, 1H), 7.02 (dd, J=8.8, 2.2 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H),2.83 (s, 3H), 1.82 (s, 2H), 1.32 (s, 6H), 1.29 (s, 6H); ¹³C NMR (101MHz, CDCl₃): δ 179.4, 145.6, 144.34, 144.25, 135.4, 124.9, 124.4, 123.2(br), 123.1, 122.7, 112.8, 54.6, 52.0, 31.51, 31.45, 31.0, 28.0. Anal.Calcd. for C₂₁H₂₆N₄O₂S: C, 63.28; H, 6.57; N, 14.06. Found: C, 63.06; H,6.58; N, 13.92.

General Procedure for the Preparation of Members of 13

To a stirred solution of 60 (0.2 g, 0.86 mmol) in THF (10 mL) was addedportion-wise lithium aluminum hydride (65.0 mg, 1.72 mmol) at 0° C. Thereaction was stirred at room temperature for 4 h, quenched withsaturated Na₂SO₄ at 0° C., filtered through CELITE and extracted withEtOAc (20 mL). The organic layer was washed with water, saturated NaCl,dried (Na₂SO₄), filtered and concentrated to give 70 as a brown oil. Theresidue was dissolved in THF (5 mL) and the solution was added dropwiseat room temperature to an isocyanate or isothiocyanate (0.86 mmol) inTHF. When TLC analysis indicated the disappearance of 60, the reactionmixture was concentrated under vacuum and purified by columnchromatography (EtOAc in hexanes gradient). Concentration of the majorfraction and crystallization from a DCM/ether mixture (2:8) afforded13a-f all of which were solids and gave the appropriate IR, NMR, andelemental analyses as well as displaying sharp melting points.

1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-nitrophenyl)urea(13a)

Yield: 0.27 g (0.69 mmol, 80%) as a yellow solid, mp 215-217° C.; IR(nujol): 3473, 3251, 1659, 1556 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.27(s, 1H), 8.51 (s, 1H), 8.17 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H),7.27 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 5.17 (d,J=6.4 Hz, 1H), 3.23 (d, J=6.4 Hz, 1H), 2.71 (s, 3H), 1.26 (s, 3H), 1.23(s, 3H), 1.16 (s, 3H), 1.06 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆): δ151.5, 146.2, 140.0, 139.8, 132.1, 128.0, 124.5, 117.9, 117.1, 116.5,111.4, 78.2, 57.7, 37.2, 30.9, 28.8, 26.5, 22.9, 17.6. Anal. Calcd. forC₂₁H₂₆N₄O₄: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.62; H, 6.81; N,14.16.

1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-(3-(4-nitrophenyl)thiourea(13b)

Yield: 0.22 g (0.53 mmol, 62%) as a yellow solid, mp 161-163° C.; IR(nujol): 3444, 1645, 1377 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 10.1 (s,1H), 10.0 (s, 1H), 8.17 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 7.23(s, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 5.21 (d, J=6.3Hz, 1H), 3.23 (d, J=6.4 Hz, 1H), 2.74 (s, 3H), 1.25 (s, 6H), 1.15 (s,3H), 1.09 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆): δ 177.9, 146.0, 141.4,141.3, 131.5, 127.4, 123.7, 122.2, 121.3, 120.5, 110.9, 77.9, 57.9,37.1, 31.0, 28.5, 26.8, 22.9, 17.9. Anal. Calcd. for C₂₁H₂₆N₄O₃S: C,60.85; H, 6.32; N, 13.52. Found: C, 60.58; H, 6.42; N, 13.71.

1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea(13c)

Yield: 0.26 g (0.61 mmol, 71%) as a brown solid; mp 213-215° C.; IR(nujol): 3308, 1647, 1605 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (s,1H), 8.38 (s, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.25(d, J=2.3 Hz, 1H), 7.10 (dd, J=8.7, 2.3 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H),5.16 (d, J=6.4 Hz, 1H), 3.22 (d, J=6.4 Hz, 1H), 2.70 (s, 3H), 1.26 (s,3H), 1.22 (s, 3H), 1.16 (s, 3H), 1.06 (s, 3H); ¹³C NMR (101 MHz,DMSO-d₆): δ151.9, 143.3, 139.6, 132.1, 128.4, 125.4 (q, J=4.4 Hz), 124.0(q, J=271.3 Hz), 120.6 (q, J=31.9 Hz), 117.7, 117.0, 116.9, 111.4, 78.2,57.7, 37.2, 30.9, 28.8, 26.5, 22.9, 17.6. Anal. Calcd. for C₂₂H₂₆F₃N₃O₂:C, 62.70; H, 6.22; N, 9.97. Found: C, 62.58; H, 6.48; N, 10.12.

1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethyl)phenyl)thiourea(13d)

Yield: 0.23 g (0.52 mmol, 60%) as a brown solid, mp 105-107° C.; IR(nujol): 3345, 1615, 1501 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.79 (s,2H), 7.73 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.20 (s, 1H), 7.11(d, J=8.7 Hz, 1H), 6.53 (d, J=8.7 Hz, 1H), 5.20 (d, J=6.4 Hz, 1H), 3.23(d, J=6.4 Hz, 1H), 2.74 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.15 (s,3H), 1.09 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆): δ 178.4, 143.1, 141.3,131.5, 127.6, 124.8 (q, J=3.6 Hz), 123.9 (q, J=252.2 Hz), 122.8 (q,J=32.0 Hz), 122.4, 121.9, 121.5, 110.9, 77.9, 57.9, 37.1, 31.0, 28.5,26.8, 22.9, 17.8. Anal. Calcd. for C₂₂H₂₆F₃N₃OS: C, 60.39; H, 5.99; N,9.60. Found: C, 60.28; H, 6.12; N, 9.47.

1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea(13e)

Yield: 0.25 g (0.57 mmol, 66%) as a brown solid, mp 188-189° C.; IR(nujol): 3467, 3310, 1648, 1554 cm⁻¹; ¹H NMR (DMSO-d₆): δ 8.68 (s, 1H),8.28 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.26 (s, 1H), 7.23 (d, J=8.7 Hz,2H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 5.16 (d,J=6.4 Hz, 1H), 3.22 (d, J=6.4 Hz, 1H) 2.70 (s, 3H), 1.26 (s, 3H), 1.22(s, 3H), 1.16 (s, 3H), 1.05 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆): δ152.2, 141.7, 139.5, 138.8, 132.1, 128.6, 121.0, 119.6 (q, J=255.1 Hz),118.5, 117.7, 117.0, 111.5, 78.2, 57.7, 37.2, 30.9, 28.8, 26.5, 22.9,17.5. Anal. Calcd. for C₂₂H₂₆F₃N₃O₃: C, 60.40; H, 5.99; N, 9.61. Found:C, 60.28; H, 6.15; N, 9.38.

1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea(13f)

Yield: 0.24 g (0.52 mmol, 60%) as a brown solid, mp 97-99° C.; IR(nujol): 3419, 1605, 1501 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 9.62 (s,1H), 9.55 (s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.17(s, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.52 (d, J=8.8 Hz, 1H), 5.19 (d, J=6.4Hz, 1H), 3.22 (d, J=6.4 Hz, 1H), 2.73 (s, 3H), 1.25 (s, 3H), 1.24 (s,3H), 1.14 (s, 3H), 1.09 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆): δ 179.8,144.8, 142.4, 139.5, 132.6, 128.7, 125.5, 123.7, 122.7, 121.5, 121.3 (q,J=255.5 Hz), 112.0, 79.0, 58.9, 38.2, 32.0, 29.6, 27.8, 23.9, 18.9.Anal. Calcd. for C₂₂H₂₆F₃N₃O₂S: C, 58.26; H, 5.78; N, 9.27. Found: C,58.34; H, 5.57; N, 9.31.

Other Syntheses and Analyses Relating to Schemes 4-15 The FollowingSyntheses and Analyses Pertain to Reactions Relevant to Scheme 4 Phenyl3-methylbut-2-enoate (15)

To an oil-free suspension of NaH (1.34 g, 56.0 mmol) in anhydrous THF(20 mL) at 0° C. (ice bath) was added over a 5-min period with stirringa solution of phenol (14, 5.0 g, 53 mmol) in THF (55 mL). The solutionwas stirred for 10 min and treated with a solution of3-methyl-2-butenoyl chloride (7.0 g, 59 mmol) in THF (25 mL) over a5-min period at 0° C., and was then allowed to warm to room temperaturefor 3 h. The white suspension was transferred to a separatory funnelcontaining water (150 mL) and acetic acid (1 mL) and was gently shaken.The mixture was extracted with ether (150 mL), and the extract waswashed with saturated NaCl (3×100 mL), dried (MgSO₄), filtered, andconcentrated to give a light yellow oil. The product was purified on a40-cm×2.5-cm silica gel column eluted with 10% ether in hexanes to give15 (8.4 g, 89%) as a colorless oil. IR: 1738, 1653 cm⁻¹; ¹H NMR (400MHz, CDCl₃): δ 7.38 (t, J=7.9 Hz, 2H), 7.20 (t, J=7.8 Hz, 1H), 7.10 (d,J=8.0 Hz, 2H), 5.91 (m, 1H), 2.22 (d, J=1.8 Hz, 3H), 1.96 (d, J=1.8 Hz,3H); ¹³C NMR (101 MHz, CDCl₃): δ 164.9, 159.9, 150.7, 129.3, 125.5,121.8, 115.3, 27.6, 20.5.

4,4-Dimethylchroman-2-one (16)

Into a 500-mL, three-necked, round-bottomed flask equipped with a stirbar, an addition funnel and a condenser (drying tube) was placeddichloromethane (DCM, 164 mL) to which was added AlCl₃ (9.87 g, 74.0mmol). The resulting suspension was stirred and cooled to 0° C. (icebath), and a solution of 15 (7.4 g, 42.0 mmol) in DCM (40 mL) was addeddropwise. The reaction was gradually warmed to room temperature, andstirring was continued for 72 h. The resulting brown solution was addedto a mixture of ice and saturated NaCl, the layers were separated, andthe aqueous layer was extracted with DCM (100 mL). The combined organiclayers were washed with saturated NaCl (2×75 mL), dried (MgSO₄),filtered, and concentrated to give a brown oil, which was purified on a40 cm×2.5 cm silica gel column eluted with 10% ether in hexanes to give16 (5.00 g, 68%) as a colorless oil. IR: 1769 cm⁻¹; ¹H NMR (400 MHz,CDCl₃): δ 7.33 (dd, J=7.4, 1.7 Hz, 1H), 7.25 (td, J=7.9, 1.7 Hz, 1H),7.15 (td, J=7.5, 1.4 Hz, 1H), 7.05 (dd, J=8.0, 1.4 Hz, 1H), 2.62 (s,2H), 1.36 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 168.1, 150.6, 131.7,128.2, 124.8, 124.4, 117.1, 45.6, 33.2, 27.6.

2-(4-Hydroxy-2,4-dimethylpentan-2-yl)phenol (17)

A solution of 15 (2.5 g, 14.2 mmol) in dry ether (40 mL) was placed in a250-mL, three-necked, round-bottomed flask equipped with a stir bar, aseptum, and a condenser. The solution was cooled to −45° C. (dryice/acetonitrile bath), and an ether solution of methyllithium (1.6 M,22.2 mL, 35.5 mmol) was added over 20 min. The reaction was stirred for18 h with gradual warming to room temperature. The reaction wascarefully poured into a mixture of ice and saturated NH₄Cl and shaken.The layers were separated, and the aqueous layer was washed with ether(2×50 mL). The combined ether layers were washed with saturated NH₄Cland water, dried (MgSO₄), filtered, and concentrated under vacuum. Theresulting oil solidified on standing at room temperature. The solid wastriturated with 1% ether in pentane and filtered to give 17 (2.72 g,92%) as a white solid, mp 86-88° C. IR: 3540, 3259, 1372, 753 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 7.29 (dd, J=7.8, 1.7 Hz, 1H), 7.07 (td, J=7.7,1.7 Hz, 1H), 6.88 (td, J=7.5, 1.4 Hz, 1H), 6.65 (br s, 1H), 6.62 (dd,J=7.9, 1.4 Hz, 1H), 2.22 (s, 2H), 1.74 (br s, 1H), 1.48 (s, 6H), 1.12(s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 154.9, 134.4, 127.8, 127.5, 120.7,117.5, 73.2, 52.4, 37.5, 31.02, 30.95.

2,2,4,4-Tetramethylchroman (18)

A 50-mL, one-necked, round-bottomed flask was charged concentratedphosphoric acid (10 mL). The acid was heated to 100° C., 17 (2.08 g 10mmol) was added, and the mixture was stirred for 1 h. The crude reactionmixture was cooled, diluted with water, and extracted with ether (3×25mL). The combined organic layers were washed with saturated NaHCO₃ andsaturated NaCl, dried (MgSO₄), filtered, and concentrated under vacuum.The resulting oil was passed through a 15 cm×2.5 cm column of silica geleluted with hexanes to give 18 (1.81 g, 95%) as a colorless oil. IR:1367, 753 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.19 (dd, J=7.7, 1.4 Hz, 1H),6.99 (td, J=7.9, 1.4 Hz, 1H), 6.83 (t, J=7.5 Hz, 1H), 6.72 (d, J=8.0 Hz,1H), 1.76 (s, 2H), 1.28 (s, 6H), 1.27 (s, 6H); ¹³C NMR (101 MHz, CDCl₃):δ 152.5, 131.5, 127.0, 126.8, 120.6, 117.9, 74.3, 49.3, 32.8, 30.8,28.6.

2,2,4,4-Tetramethyl-6-nitrochroman (19) and2,2,4,4-tetramethyl-8-nitrochroman (20)

A 25-mL, three-necked, round-bottomed flask equipped with a magneticstirrer, an addition funnel, and a nitrogen inlet was charged with 18(190 mg, 1.0 mmol) and freshly distilled acetic anhydride (625 μL). Thesolution was cooled to −10° C. (ice/salt bath), and a cold solution ofconcentrated nitric acid (77 μL) in acetic anhydride (625 μL) was addeddropwise over 15 min. The reaction was stirred at −5° C. for 30 min andthen diluted with DCM and washed with saturated NaHCO₃. The NaHCO₃ washwas back-extracted with 20 mL of DCM, and the combined organic layerswere washed with water and saturated NaCl, dried (MgSO₄), filtered, andconcentrated under vacuum. The crude product was purified by preparativethin layer chromatography on a silica gel plate (20 cm×20 cm) using 1%ether in hexanes to give three bands: band 1, recovered 18 (4 mg, 2%) asa colorless oil; band 2, the 6-nitro isomer 19 (78 mg, 33%) as a whitesolid, mp 64-65° C.; and band 3, the 8-amino isomer 20 (96 mg, 41%) as awhite solid, mp 71-72° C. The spectral data for 19 were: IR: 1517, 1339cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.50 (d, J=2.7 Hz, 1H), 8.00 (dd,J=9.0, 2.7 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 1.89 (s, 2H), 1.49 (s, 6H),1.48 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 158.5, 141.4, 132.0, 123.6,123.2, 118.5, 76.4, 48.1, 32.7, 31.2, 28.5. The spectral data for 20were: IR: 1526, 1365 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=8.0,1.6 Hz, 1H), 7.48 (dd, J=7.8, 1.6 Hz, 1H), 6.92 (t, J=7.9 Hz, 1H), 1.89(s, 2H), 1.45 (s, 6H), 1.43 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 146.6,140.8, 135.2, 130.9, 122.7, 119.6, 76.9, 48.4, 32.6, 31.4, 28.4.

6-Amino-2,2,4,4-tetramethylchroman (21)

To a stirred solution of 19 (120 mg, 0.51 mmol) in absolute ethanol (5mL) in a 50-mL, round-bottomed flask was added 5% Pd/C (10 mg), and themixture was hydrogenated under 1 atm (balloon) of H₂ gas for 1.5 h. Thereaction was diluted with ether, filtered through CELITE® to remove thecatalyst, and concentrated. The resulting red oil was purified bypassing through a plug of silica using 10-20% ether in hexanes to give21 as a yellow oil (71 mg, 68%). IR: 3435, 3358, 3221, 1627, 1498 cm⁻¹;¹H NMR (400 MHz, CDCl₃): δ 6.63 (s, 1H), 6.61 (d, J=7.8 Hz, 1H), 6.47(dd, J=7.8, 2.7 Hz, 1H), 3.50 (br s, 2H), 1.78 (s, 2H), 1.31 (s, 6H),1.29 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 145.4, 139.5, 132.3, 118.3,114.9, 113.4, 73.8, 49.3, 32.6, 31.0, 28.4.

Syntheses and Analysis of Compounds Shown in Scheme 52-(4-Hydroxy-2-methylbutan-2-yl)phenol (22)

A 250-mL, three-necked, round-bottomed flask equipped with a stir bar, aseptum, and a condenser was charged with a suspension of 4.18 g (110mmol) of lithium aluminum hydride in dry THF (50 mL). The solution wascooled to 0° C. (ice bath), and a solution of 16 (5.0 g, 28.4 mmol) indry THF (50 mL) was added over 1 h. The resulting suspension was stirredat room temperature for 1 h and heated at reflux for 2 h and then cooledin ice. The excess lithium aluminum hydride was destroyed by dropwiseaddition of 20% ethyl acetate in THF (8 mL). The thick suspension wascarefully poured into 150 mL of 1 M H₂SO₄/ice. This mixture wassaturated with NaCl and extracted with ether (3×150 mL). The combinedextracts were washed with saturated NaCl (3×100 mL), dried (Na₂SO₄),filtered, and concentrated under vacuum. The resulting oil solidifiedupon standing at room temperature. The solid was triturated with 1%ether in pentane and filtered to give 22 (4.60 g, 90%) as a white solid,mp 108-110° C. IR: 3531, 3251 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.21 (d,J=8.0 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.62 (d,J=8.0 Hz, 1H), 5.85 (br s, 1H), 3.53 (t, J=7.0 Hz, 2H), 2.32 (t, J=7.0Hz, 2H), 1.41 (s, 6H), one alcohol proton not observed; ¹³C NMR (101MHz, CDCl₃): δ 154.4, 133.7, 127.6, 127.4, 120.5, 116.6, 61.0, 42.9,36.7, 28.7.

4,4-Dimethychroman (23)

A solution of 4.25 g (23.6 mmol) of 22 in pyridine (50 mL) was stirredand cooled at 0° C. (ice bath) and then treated with 3.59 g (31.3 mmol)of methanesulfonyl chloride. The reaction was stirred at 0° C. for 1 hand was then poured into saturated NaCl (150 mL) and extracted withether (3×75 mL). The combined extracts were washed with dilute NaCl (75mL), 1 M HCl (2×175 mL), and dilute NaCl (2×75 mL), dried (MgSO₄) andconcentrated to give the mesylate as a yellow oil. The crude mesylatewas dissolved in dioxane (50 mL), and the solution was stirred with 1 MNaOH (62.5 mL) at room temperature for 3 h. The two-phased mixture wasdiluted with saturated NaCl and extracted with ether (3×75 mL). Thecombined extracts were washed with saturated NaCl (75 mL), dried(MgSO₄), filtered, and concentrated under vacuum. The crude product waspurified by passing it through a plug of silica gel with 3% ether inhexanes to give 23 (3.64 g, 95%) as a colorless oil. IR: 3065, 3031,1607, 1579, 1486 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.26 (d, J=7.7 Hz,1H), 7.06 (t, J=7.8 Hz, 1H), 6.87 (t, J=7.9 Hz, 1H), 6.78 (d, J=8.2 Hz,1H), 4.18 (t, J=5.3 Hz, 2H), 1.83 (t, J=5.3 Hz, 2H), 1.32 (s, 6H); ¹³CNMR (101 MHz, CDCl₃): δ 153.6, 131.6, 127.0, 126.9, 120.4, 116.9, 63.0,37.7, 31.1, 30.5.

4,4-Dimethyl-6-nitrochroman (24) and 4,4-dimethyl-8-nitrochroman (25)

A 25-mL, three-necked, round-bottomed flask equipped with a magneticstirrer, an addition funnel, and a nitrogen inlet was charged with 23(1.10 g, 6.8 mmol) and freshly distilled acetic anhydride (4.25 mL). Thesolution was cooled to −10° C. (ice/salt bath), and a cold solution ofconcentrated nitric acid (0.52 mL) in acetic anhydride (4.25 mL) wasadded dropwise over 30 min. The reaction was stirred at −5° C. for 30min and was then diluted with DCM and washed with saturated NaHCO₃. TheNaHCO₃ wash was back-extracted with DCM (20 mL), and the combinedorganic layers were washed with water and saturated NaCl, dried (MgSO₄),filtered, and concentrated under vacuum to give 1.25 g of a yellow oilconsisting of a 45:55 mixture of 24 and 25. As this product mixture wasdifficult to purify by chromatography, it was carried on to the 6- and8-amino compounds, 26 and 27, respectively, before purification.

6-Amino-4,4-dimethylchroman-6-amino (26) and8-amino-4,4-dimethylaminochroman (27)

A solution of the mixture of 24 and 25 [1.25 g (ca. 6.04 mmol)] wasdissolved in a mixture of 90 mL of ethanol and 20 mL of water. To thestirred solution was added ammonium chloride (0.33 g, 6.17 mmol) andiron powder (1.10 g, 19.6 mmol), and the mixture was heated at 85° C.for 2 h. The reaction was filtered through CELITE®, treated with NaHCO₃(50 mL) and extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with saturated NaCl, dried (Na₂SO₄), filtered, andconcentrated under vacuum. The resulting brown oil was purified on a30×2.0 cm silica gel column slurry packed in hexane containingincreasing concentrations of ether (2-30%). Elution gave two bands: band1, the 8-amino isomer 27 (552 mg, 52%) as a yellow oil and band 2, the6-amino isomer 26 (451 mg, 42%) as a yellow oil. The spectral data for26 were: IR: 3429, 3352, 3230, 1620, 1498 cm⁻¹; ¹H NMR (400 MHz, CDCl₃):δ 6.69 (m, 2H), 6.52 (m, 1H), 4.22 (t, J=5.3 Hz, 2H), 3.71 (br s, 2H),1.80 (t, J=5.3 Hz, 2H), 1.30 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 141.4,135.4, 131.4, 120.1, 116.3, 112.5, 63.1, 37.9, 31.1, 30.6. The spectraldata for 27 were: IR: 3429, 3356, 3227, 1624, 1499 cm⁻¹; ¹H NMR (400MHz, CDCl₃): δ 6.62 (m, 2H), 6.53 (dd, J=8.6, 2.7 Hz, 1H), 4.11 (t,J=5.3 Hz, 2H), 3.36 (br s, 2H), 1.83 (t, J=5.3 Hz, 2H), 1.31 (s, 6H);¹³C NMR (101 MHz, CDCl₃): δ 146.7, 139.4, 132.3, 117.4, 115.1, 113.7,62.9, 38.0, 31.2, 30.7.

The Following Pertains to Scheme 62-(4-Ethyl-4-hydroxy-2-methylhexan-2-yl)phenol (28)

Compound 28 was prepared on a 10.0 mmol scale from known4,4-dimethylchroman-2-one (16) and 2.5 eq of ethylmagnesium bromide inether and was used directly. The yield of 28 was 1.82 g (7.71 mmol, 77%)as a white solid, mp 109-111° C.; IR: 3532, 3206 cm⁻¹; ¹H NMR (400 MHz,CDCl₃): δ 7.29 (d, J=7.8 Hz, 1H), 7.20 (br s, 1H), 7.03 (t, J=7.5 Hz,1H), 6.86 (t, J=7.5 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 2.14 (s, 2H), 1.98(br s, 1H), 1.48 (s, 6H), 1.42 (q, J=7.5 Hz, 4H), 0.78 (t, J=7.4 Hz,6H); ¹³C NMR (101 MHz, CDCl₃): δ 155.9, 134.6, 127.6, 127.5, 120.5,117.5, 77.5, 48.3, 37.3, 31.4, 31.3, 8.0.

2,2-Diethyl-4,4-dimethylchroman (29)

Compound 29 was prepared on a 6.00 mmol scale from 28 and purifiedaccording to a procedure described for the preparation of2,2,4,4-tetramethylchroman (18) as found in the literature [Journal ofMedicinal Chemistry, 2004, Vol. 47 pages 1008-1017, and the articleentitled “Novel Heteroarotinoids as Potential Antagonists ofMycobacterium bovis BCG” by C. W. Brown, S. Liu, J. Klucik, K. D.Berlin. and P. J. Brennan]. The yield of 2,2-diethyl-4,4-dimethylchroman(29) was 1.12 g (5.14 mmol, 86%) as a colorless oil; IR: 1607, 1583cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.23 (d, J=7.5 Hz, 1H), 7.04 (t, J=8.0Hz, 1H), 6.86 (t, J=7.5 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 1.78 (s, 2H),1.70 (m, 2H), 1.56 (m, 2H), 1.32 (s, 6H), 0.88 (t, J=7.5 Hz, 6H); ¹³CNMR (101 MHz, CDCl₃): δ 152.7, 132.3, 127.1, 126.5, 120.7, 118.1, 78.9,45.6, 33.2, 30.6, 29.4, 8.0.

6-Amino-2,2-diethyl-4,4-dimethylchroman (32) and8-amino-2,2-diethyl-4,4-dimethylchroman (33)

2,2-Diethyl-4,4-dimethylchroman (29) was nitrated in the usual manner ona 5.00 mmol scale using nitric acid in acetic anhydride at −10° C. asdescribed for 2,2,4,4-tetramethylchroman (18) to give a mixture of the6-isomer 30 and the 8-nitro isomer 31 as a yellow oil. Since the nitroderivatives were difficult to separate, the mixture was reduced asdescribed for the preparation of 26/27, precursors of series 4 and 5,using ammonium chloride in aqueous ethanol to give the 6-amino (32) and8-amino (33) compounds in a 6.2:1 ratio (86% crude yield). These isomerswere separated on a 30 cm×2.5 cm silica gel column eluted withincreasing concentrations of ether in hexanes to give two bands: band 1,the 8-amino isomer (33, 127 mg, 0.55 mmol, 11%) eluted with 10% ether inhexanes and solidified as a light brown oil; band 2, the 6-amino isomer(32, 792 mg, 3.40 mmol, 68%) eluted with 30% ether in hexanes as a tanoil. The spectral data for 33 were: IR: 3466, 3375, 3184, 1611 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 6.75-6.67 (complex, 2H), 6.55 (dd, J=7.2, 2.0Hz, 1H), 3.75 (br s, 2H), 1.80 (s, 2H), 1.76 (m, 2H), 1.60 (m, 2H), 1.32(s, 6H), 0.90 (t, J=7.5 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 139.9,136.1, 132.0, 120.2, 115.9, 112.4, 79.1, 45.2, 32.9, 30.6, 29.1, 8.0.The spectral data for 32 were: IR: 3429, 3355, 3221, 1624 cm⁻¹; ¹H NMR(400 MHz, CDCl₃): δ 6.63 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 6.46 (dd,J=8.4, 2.8 Hz, 1H), 3.27 (br s, 2H), 1.74 (s, 2H), 1.70 (m, 2H), 1.51(m, 2H), 1.30 (s, 6H), 0.87 (t, J=7.5 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃):δ 145.5, 139.5, 133.4, 118.5, 114.8, 113.3, 78.6, 45.4, 32.8, 30.8,29.1, 7.8.

The Following Pertains to Scheme 7 Phenyl 3,3-diethylacrylate (34)

This compound was prepared from phenol (14) and 3-ethyl-2-pentenoylchloride (obtained by treatment of 3-ethyl-2-pentenoic acid with SOCl₂)on a 53 mmol scale and was purified by column chromatography on a 40cm×2.5 cm silica gel column eluted with 8% ether in hexane. The yield of34 was 9.96 g (48.8 mmol, 92%) as a colorless oil; IR: 1738, 1640, 1593,1200 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.37 (t, J=7.8 Hz, 2H), 7.20 (t,J=7.4 Hz, 1H), 7.09 (d, J=7.8 Hz, 2H), 5.85 (s, 1H), 2.67 (q, J=7.5 Hz,2H), 2.27 (qd, J=7.4, 1.2 Hz, 2H), 1.13 (t, J=7.4 Hz, 3H), 1.10 (t,J=7.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 170.8, 164.8, 150.8, 129.3,125.7, 121.8, 112.8, 31.1, 25.8, 13.0, 12.0.

4,4-Diethylchroman-2-one (35)

This compound was prepared on a 44 mmol scale as described for4,4-dimethylchroman-2-one (23) and was purified on a 40 cm×2.5 cm silicagel column eluted with 8% ether in hexane. The yield of 35 was 3.12 g(15.2 mmol, 35%) as a light yellow oil; IR: 1776, 1609, 1585, 1202 cm⁻¹;¹H NMR (400 MHz, CDCl₃): δ 7.28-7.23 (m, 1H), 7.20 (dd, J=7.8, 1.8 Hz,1H), 7.15 (td, J=7.8, 1.1 Hz, 1H), 7.07 (dd, J=7.8, 1.1 Hz, 1H), 2.63(s, 2H), 1.79-1.61 (complex, 4H), 0.82 (t, J=7.4 Hz, 6H); ¹³C NMR (101MHz, CDCl₃): δ 168.9, 151.6, 128.1, 128.0, 126.2, 124.2, 117.3, 39.9,38.5, 29.9, 8.1.

2-(3-Ethyl-5-hydroxy-5-dimethylhexan-3-yl)phenol (36)

This compound was prepared on a 4.90 mmol scale from4,4-diethylchroman-2-one (35) and methylmagnesium bromide in ether (−45°C.→rt) and was used without further purification. The yield of 36 was1.02 g (4.32 mmol, 88%) as a light yellow oil; IR: 3538, 3269, 1601cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.29 (dd, J=8.0, 1.7 Hz, 1H), 7.06 (td,J=7.9, 1.1 Hz, 1H), 6.89 (td, J=7.7, 1.1 Hz, 1H), 6.59 (d, J=7.8 Hz,1H), 2.18 (s, 2H), 2.10 (m, 2H), 1.82 (m, 2H), 1.63 (br s, 2H), 1.10 s,6H), 0.72 (t, J=7.4 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 155.0, 132.8,129.1, 127.3, 120.6, 117.5, 73.2, 45.9, 43.2, 31.1, 26.9, 7.9.

4,4-Diethyl-2,2-dimethylchroman (37)

This compound was prepared and purified on a 4.00 mmol scale accordingto the procedure described for the preparation of2,2,4,4-tetramethylchroman (18). The yield of 37 was 0.78 g (3.60 mmol,90%) as a colorless oil; IR: 1604, 1597, 1483, 1381, 1367, 745 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 7.16 (dd, J=7.8, 1.7 Hz, 1H), 7.07 (ddd, J=8.2,7.3, 1.7 Hz, 1H), 6.89 (td, J=7.3, 1.7 Hz, 1H), 6.79 (dd, J=8.2, 1.7 Hz,1H), 1.78 (s, 2H), 1.76-1.61 (complex, 4H), 1.34 (s, 6H), 0.75 (t, J=7.4Hz, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 154.0, 130.3, 126.9, 126.7, 120.5,117.9, 74.3, 40.2, 37.4, 33.5, 29.1, 8.4.

6-Amino-4,4-diethyl-2,2-dimethylchroman (40) and8-amino-4,4-diethyl-2,2-dimethyl-chroman (41)

4,4-Diethyl-2,2-dimethylchroman (37) was nitrated on a 3.50 mmol scaleusing nitric acid in acetic anhydride at −10° C. as described for2,2,4,4-tetramethylchroman (18) to give a mixture of the 6-nitro (38)and 8-nitro (39) isomers as a yellow oil. Since the nitro derivativeswere difficult to separate, the mixture was reduced as described for thepreparation of 26/27 using ammonium chloride in aqueous ethanol to givethe 6- and 8-amino compounds (40 and 41, respectively) in a 1:1.2 ratio(84% crude yield). These were separated on a 30 cm×2.5 cm silica gelcolumn eluted with increasing concentrations of ether in hexane to givetwo bands: band 1, the 8-amino isomer (401 343 mg, 1.47 mmol, 42%)eluted with 10% ether in hexanes and solidified as a tan solid, mp37-38° C.; band 2, the 6-amino isomer (40, 294 mg, 1.26 mmol, 36%)eluted with 30% ether in hexanes as a tan oil. The spectral data for 41were: IR: 3471, 3374, 3194, 1612 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.72(t, J=7.7 Hz, 1H), 6.59 (dd, J=7.9, 1.6 Hz, 1H), 6.56 (dd, J=7.6, 1.6Hz, 1H), 3.73 (br s, 2H), 1.77 (s, 2H), 1.77-1.57 (complex, 4H), 1.35(s, 6H), 0.75 (t, J=7.4 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 141.6,136.1, 130.2, 120.2, 116.5, 112.4, 74.6, 40.4, 37.7, 33.2, 29.2, 8.5.The spectral data for the 40 were: IR: 3434, 3356, 3220, 1626 cm⁻¹; ¹HNMR (400 MHz, CDCl₃): δ 6.62 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.7 Hz, 1H),6.48 (dd, J=8.4, 2.7 Hz, 1H), 3.37 (bs, 2H), 1.73 (s, 2H), 1.72-1.56(complex, 4H), 1.30 (s, 6H), 0.76 (t, J=7.4 Hz, 6H); ¹³C NMR (101 MHz,CDCl₃): δ 147.1, 139.5, 131.3, 118.3, 114.6, 113.7, 73.9, 40.4, 37.7,33.3, 28.9, 8.4.

The Following Pertains to Scheme 8

2-(3,5-Diethyl-5-hydroxyheptan-3-yl)phenol (42) and2,2,4,4-tetraethylchroman (43) This compound was prepared from lactone35 by treatment with 2.5 eq of ethylmagnesium bromide to generate2-(3,5-diethyl-5-hydroxyheptan-3-yl)phenol (42), followed by ringclosure with H₃PO₄ to promote formation of 43. The compound was purifiedby column chromatography to give the chroman as a colorless oil. A smallimpurity was present and could not be removed. The slightly crude 43 wascarried on to the next step.

2,2,4,4-Tetraethyl-6-nitrochroman (44) and2,2,4,4-tetraaethyl-8-nitrochroman (45)

This compound was prepared by treatment of 43 with nitric acid in aceticanhydride at −10° C. This reaction gave the C-6 and C-8 nitratedproducts 44 and 45, respectively, which were difficult to separate.Purification by preparative thin layer chromatography gave the C-6nitrated product 44 (35%) as a light yellow oil. The C-8 nitratedproduct 45 co-eluted with the impurity cited above and was discarded.Spectral data for 44 were: IR: 1604, 1583, 1618, 1339, 1264 cm⁻¹; ¹H NMR(400 MHz, CDCl₃): δ 8.10 (d, J=2.7 Hz, 1H), 7.98 (dd, J=8.9, 2.7 Hz,1H), 6.86 (d, J=8.9 Hz, 1H), 1.80 (s, 2H), 1.80-1.54 (complex, 8H), 0.90(t, J=7.4 Hz, 6H), 0.77 (t, J=7.5 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃): δ160.6, 141.8, 131.9, 123.9, 123.5, 118.8, 81.5, 37.9, 35.9, 34.0, 30.3,8.7, 8.2.

2,2,4,4-Tetraethylchroman-6-amine (46)

Nitrochroman 44 (1.00 g, 3.43 mmol) was reduced as described previouslyfor 24 using iron powder and ammonium chloride in aqueous ethanol togive the amine (46, 816 mg, 3.12 mmol, 91%) as a light yellow oil thatdarkened on exposure to air. IR: 3434, 3354, 3218, 1623, 1495, 1228cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.65 (d, J=8.4 Hz, 1H), 6.51 (d, J=2.7Hz, 1H), 6.48 (dd, J=8.4, 2.7 Hz, 1H), 3.36 (br s, 2H), 1.69 (s, 2H),1.76-1.44 (complex, 8H), 0.86 (t, J=7.5 Hz, 6H), 0.75 (t, J=7.4 Hz, 6H);¹³C NMR (101 MHz, CDCl₃): δ 147.0, 139.5, 132.4, 118.4, 114.3, 113.7,78.7, 37.8, 37.6, 33.3, 29.6, 8.4, 7.8.

The Following Pertains to Scheme 9N-(4-Bromophenyl)-3-methylbut-2-enamide (48)

A solution of 3-methylbut-2-enoyl chloride (3.4 mL, 29.0 mmol) in CHCl₃(25 mL) was added dropwise to a stirred solution of 4-bromoaniline (47,10 g, 58.1 mmol) in CHCl₃ (250 mL). The resulting cloudy reactionmixture was refluxed for 5 h, and then was cooled to room temperatureand filtered through CELITE®. The filtrate was washed with 1 M HCl (100mL), saturated NaHCO₃, and saturated NaCl, dried (MgSO₄), filtered,concentrated under vacuum and recrystallized from ethanol to afford 48as a white solid (5.5 g, 21.8 mmol, 75%), mp 118-119° C.; IR: 3294,1663, 1643, 826 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.42 (m, 4H), 7.23 (brs, 1H), 5.69 (s, 1H), 2.21 (s, 3H), 1.89 (s, 3H); ¹³C NMR (101 MHz,CDCl₃): δ 165.0, 154.4, 137.3, 131.9, 121.3, 118.3, 116.5, 27.5, 20.0.

6-Bromo-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (49)

To a stirred solution of 48 (5.0 g, 19.6 mmol) in 1,2-dichloroethane wasadded AlCl₃ (3.9 g, 29.5 mmol) portion-wise, and the mixture was heatedto reflux for 1 h. The reaction was cooled to 0° C., quenched withice-cold water (20 mL), filtered through CELITE and washed with DCM(2×50 mL). The combined organic extracts were washed with saturatedNaHCO₃ and saturated NaCl, dried (MgSO₄), filtered and concentratedunder vacuum. Column chromatography eluted with increasingconcentrations of ether in hexanes afforded 49 as a brown solid (3.8 g,14.9 mmol, 76%), mp 151-153° C.; IR: 3201, 1681, 1488, 1368 cm⁻¹; ¹H NMR(400 MHz, CDCl₃): δ 9.36 (s, 1H), 7.39 (s, 1H), 7.27 (d, J=8.4 Hz, 1H),6.75 (d, J=8.4 Hz, 1H), 2.48 (s, 2H), 1.34 (s, 6H); ¹³C NMR (101 MHz,CDCl₃): δ 171.2, 135.1, 134.6, 130.4, 127.7, 117.5, 116.1, 44.9, 34.1,27.5.

6-Bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline (50)

To a stirred, ice-cooled solution of 49 (3.5 g, 13.8 mmol) in distilledtoluene (35 mL) was added dropwise borane-dimethyl sulfide complex (1.4mL, 14.4 mmol), and the mixture was refluxed for 3 h. The reaction wascooled to room temperature and quenched carefully by dropwise additionof 10% Na₂CO₃ (10 mL). The resulting biphasic mixture was stirred atroom temperature for 15 min, and the layers were separated. The organicphase was dried (MgSO₄), filtered and concentrated under vacuum to give50 as a colorless oil (3.0 g, 12.4 mmol, 90%); IR 3414, 1495, 1282 cm⁻¹;¹H NMR (400 MHz, CDCl₃): δ 7.29 (d, J=2.3 Hz, 1H), 7.07 (dd, J=8.3, 2.3Hz, 2H), 6.52 (d, J=8.5 Hz, 1H), 3.33 (t, J=5.8 Hz, 2H), 1.76 (t, J=5.8Hz, 2H), 1.29 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 140.4, 133.7, 129.5,129.4, 117.1, 110.6, 38.4, 36.4, 32.0, 30.8.

tert-Butyl 6-bromo-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-carboxylate(51)

A THF (50 mL) solution containing 50 (3.0 g, 12.4 mmol) was cooled to−78° C., and 2.5 M n-BuLi (6 mL, 15.0 mmol) was added dropwise over aperiod of 30 min. The solution was stirred for 30 min and di-tert-butyldicarbonate (3.3 g, 14.9 mmol) in THF (15 mL) was added dropwise over aperiod of 30 min. The reaction mixture was gradually allowed to attainroom temperature with stirring for 18 h, and then it was cooled to 0° C.The mixture was quenched by dropwise addition of saturated NH₄Clsolution (20 mL). The layers were separated, and the aqueous phase wasextracted with ether (2×50 mL). The combined organic extracts were dried(MgSO₄), filtered, concentrated and purified by column chromatography(ether in hexanes gradient) to provide 51 as a brown oil (3.8 g, 11.4mmol, 92%); IR: 1679, 1483, 1367, 1152 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ7.52 (d, J=6.6 Hz 1H), 7.36 (d, J=2.4 Hz, 1H), 7.21 (dd, J=6.6, 2.3 Hz,1H), 3.72-3.69 (m, 2H), 1.74-1.71 (m, 2H), 1.51 (s, 9H), 1.28 (s, 6H);¹³C NMR (101 MHz, CDCl₃): δ 153.6, 140.2, 136.3, 128.7, 128.6, 126.0,116.4, 81.1, 41.6, 38.1, 33.4, 29.9, 28.4.

tert-Butyl-6-azido-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-carboxyate(52) and tert-butyl6-amino-4,4-dimethyl-3,4-dihydroquinoline-1(2H)-carboxylate (53)

A mixture of 51 (3.5 g, 10.3 mmol), sodium azide (1.3 g, 20.6 mmol), CuI(0.2 g, 1.03 mmol), L-proline (0.35 g, 3.1 mmol), NaOH (0.12 g, 3.14mmol) and ethanol/water (7:3, 20 mL) was heated to 90° C. in a 35-mLChemglass pressure vessel (No. CG-1880-02) for 18 h. The reactionmixture was cooled to room temperature, filtered through CELITE® andwashed with EtOAc (50 mL). The filtrate was washed with water (2×30 mL)and saturated NaCl, dried (MgSO₄) and concentrated under vacuum toprovide 52 as a brown oil. This oil was quickly dissolved in methanol(100 mL), transferred to a 250-mL, round-bottomed flask, and 10% Pd/C(0.3 g, 10% w/w) was added under a nitrogen atmosphere. The reactionvessel was flushed with H₂ gas, and stirred under H₂ (1 atm, balloon) atroom temperature for 6 h. The catalyst was removed by filtration throughCELITE® and washed with methanol (25 mL). The filtrate was concentratedand purified by column chromatography (hexanes:ether; 4:1) to afford 53(1.8 g, 6.4 mmol, 62%) as a brown oil. IR: 3448, 3362, 1685, 1503, 138cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.28 (d, J=1.6 Hz, 1H), 7.12 (d, J=7.2Hz, 1H), 7.03 (td, J=7.2, 1.6 Hz, 1H), 3.75-3.72 (m, 2H), 1.76-1.73 (m,2H), 1.52 (s, 9H), 1.30 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 154.0,142.1, 139.1, 128.7, 125.5, 113.1, 112.2, 80.3, 41.6, 38.8, 30.2, 28.5,28.4.

Syntheses of 54 Leading to Series 9 and 10

A solution of 53 (0.2 g, 0.7 mmol) in THF (5 mL) was added to anappropriate isocyanate or isothiocyanate (0.7 mmol) in THF (2 mL) atroom temperature under nitrogen. The mixture was stirred until TLCindicated that 53 had been consumed. Evaporation of the solventgenerated each member of 54 which were dissolved in DCM. Treatment ofeach solution with trifluoroacetic acid gave a mixture which was stirreduntil TLC indicated that members of 54 were absent. The solvent wasevaporated and additional DCM was added and then was also evaporated.Water was added, and the mixture was washed with cold ether. The aqueouslayer was basified (NaHCO₃), and the mixture was extracted with ethylacetate. The extracts ere combined and washed with water, saturatedNaCl, dried, and the solvent was evaporated to give members of 9. To astirred solution of 9d (0.2 g, 0.6 mmol) in DMF in a 15 mL Chemglasspressure vessel (No. CG1880-01) was added Cs₂CO₃ (390 mg, 1.2 mmol) andmethyl iodide (1.0 mL, 16 mmol). The vessel was closed and stirring wascontinued at room temperature for 24 hours. Water was added, and themixture was filtered. The solid was stirred with ethanol for 15 minutesand filtered to give 10 as a light yellow solid (185 mg, 62%), mp249-251° C., IR: 3297, 3260, 1724, 1598, 843 cm⁻¹. ¹H NMR (400 MHz,CDCl₃): δ 9.59 (s, 1H), 9.21 (s, 1H, 8.21 (d, J=8.0 Hz, 2H), 7.88 (d,J=9.2 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.51 (d, J=9.2 Hz,1H), 3.89 (s, 6H), 3.56 (s, 6H), 2.11 (s, 2H), 1.36 (s, 6H); ¹³C NMR(101 MHz, CDCl₃): δ 151.4, 145.4, 139.7, 139.4, 135.0, 124.5, 121.3,117.4, 116.7, 59.4, 56.1, 31.6, 30.5, 26.8. Anal. Calcd. forC₂₀H₂₅IN₄O₃: C, 48.40; H, 5.08; N, 11.29. Found: C, 48.65; H, 5.23; N,11.52.

The Following Pertains to Scheme 106-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (55)

Bismuth(III) triflate (19.0 g, 30.0 mmol) was added to a solution of4-bromoaniline (47, 25.0 g, 145 mmol) in acetone (500 mL), and themixture was stirred at reflux for 3 days. The solvent was removed undervacuum, and the residue was partitioned between ether (300 mL) and water(200 mL). The layers were separated, and the aqueous phase was extractedwith ether. The combined organic extracts were washed with saturatedNaCl and evaporated under vacuum. The crude product was purified bycolumn chromatography (ether in hexanes gradient) to afford 55 as abrown solid (23 g, 89.9 mmol, 62%), mp 83-85° C.; IR: 3382, 1486, 1257,806 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.13 (d, J=2.2 Hz, 1H), 7.05 (dd,J=8.4, 2.2 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 5.33 (s, 1H), 3.71 (br s,1H), 1.95 (s, 3H), 1.26 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 142.2,130.7, 129.4, 127.6, 126.2, 123.4, 114.3, 108.6, 51.9, 30.9, 18.4.

6-Bromo-1,2,2,4-tetramethyl-1,2-dihydroquinoline (56)

Sodium hydride (4.5 g of a 60% dispersion in mineral oil, 113.0 mmol)was added to DMF (190 mL) under a nitrogen atmosphere, and the mixturewas cooled to 15° C. A solution of 55 (19.0 g, 75.3 mmol) in DMF (75 mL)was added dropwise, the mixture was stirred for 30 min, and then methyliodide (42.6 g, 18.7 mL, 300 mmol) in DMF (75 mL) was added dropwise.The reaction mixture was warmed to room temperature gradually andstirred for 18 h. The crude reaction mixture was added to water, and themixture was extracted with ether (2×100 mL). The combined organicextracts were washed with saturated NaCl, dried (MgSO₄), filtered andconcentrated to provide 56 (16.4 g, 62 mmol, 82%) as a yellow oil; IR:1488, 1406, 797 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.16 (dd, J=8.4, 2.4Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H), 5.32 (d, J=1.5Hz, 1H), 2.76 (s, 3H), 1.95 (s, 3H), 1.29 (s, 6H); ¹³C NMR (101 MHz,CDCl₃): δ 144.2, 131.2, 130.9, 127.3, 125.8, 125.2, 112.2, 108.4, 56.3,30.7, 27.1, 18.5.

6-Bromo-1,2,2,4-tetramethyl-1,2,3,4-tetrahydroquinolin-3-ol (57)

A 1.0 M borane:THF solution (97.0 mmol, 97 mL) was added dropwise to anice-cooled solution of 14 (13.0 g, 48.8 mmol) in THF (250 mL), and themixture was stirred at 15° C. for 6 h. A 1:1 solution of THF/H₂O (60 mL)was added dropwise to the reaction mixture over 30 min, followed bydropwise addition of 3 M NaOH (50 mL) over 30 min. To this mixture wasadded 30% aqueous hydrogen peroxide (16.0 mL), and stirring wascontinued at room temperature for 2 h. The crude reaction mixture waspoured into water and extracted with EtOAc (3×150 mL). The combinedorganic layers were washed with saturated NaHCO₃ and saturated NaCl,dried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude product was purified by flash chromatography (hexane/EtOAc 7:3) toafford 57 as a colorless oil (7.9 g, 27.8 mmol, 57%). IR: 3406, 1589,1490 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.24 (d, J=2.4 Hz, 1H), 7.17 (dd,J=8.8, 2.4 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 3.27 (d, J=9.4 Hz, 1H), 2.79(s, 3H), 2.76-2.68 (m, 1H); 1.90 (br s, 1H), 1.41 (d, J=6.8 Hz, 3H),1.36 (s, 3H), 1.01 (s, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 144.3, 129.9,129.7, 128.2, 113.8, 109.0, 58.0, 36.1, 31.6, 24.9, 18.1, 17.0.

6-Bromo-1,2,2,4-tetramethyl-1,2,3,4-tetrahydroquinolin-3-one (58) and6-Bromo-1,2,2,4,4-pentamethyl-1,4-dihydroquinolin-3(2H)-one (59)

DMSO (2.3 mL, 31.7 mmol) was added dropwise to a solution of oxalylchloride (1.4 mL, 17.3 mmol) in DCM (60 mL) at −60° C., and theresulting mixture was stirred for 10 min. This mixture was transferredvia syringe to a solution of 57 (4.1 g, 14.4 mmol) in DCM (60 mL) at−60° C. The mixture was stirred for 15 min, and then triethylamine (10mL, 72.0 mmol) was added dropwise over 15 min. The reaction was stirred1 h and quenched by dropwise addition of water (20 mL). The mixture wasstirred with warming to room temperature, and the layers were separated.The organic layer was washed with water (2×20 mL), dried (MgSO₄),filtered and concentrated to give 58. The crude product was useddirectly for the next step without further purification.

To a solution of 58 in THF (20 mL) was added dropwise 26% lithiumbis(trimethylsilyl)amide in THF (25 mL, 38.0 mmol) over 10 min at −50°C. The reaction was warmed to −20° C., and iodomethane (2.4 mL, 38.0mmol) in THF (20 mL) was added dropwise, and stirring was continued withwarming to room temperature for 3 h. The reaction mixture was pouredinto ice-cold water and extracted with EtOAc (2×50 mL). The combinedorganic layers were washed with saturated NaCl, dried (Na₂SO₄), filteredand concentrated under vacuum. Purification by column chromatography(hexanes/EtOAc 3:2) gave 59 (2.6 g, 8.9 mmol, 62%) as a colorless oil.IR: 1719, 1486 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.33 (dd, J=8.6, 2.3 Hz,1H), 7.29 (d, J=2.3 Hz, 1H), 6.08 (d, J=8.6 Hz, 1H), 2.83 (s, 3H), 1.45(s, 6H), 1.28 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 214.4, 144.6, 132.7,130.4, 127.5, 115.7, 112.4, 64.2, 47.6, 30.9, 23.3, 22.9.

6-Amino-1,2,2,4,4-pentamethyl-1,4-dihydroquinolin-3(2H)-one (60)

Into a 250-mL Chemglass pressure vessel (No. CG-1880-R-03) was added 59(1.9 g, 6.42 mmol), copper iodide (0.61 g, 3.2 mmol), L-proline (0.74 g,6.42 mmol), DMF (4.0 mL) and aqueous ammonia (19.0 mL). The reactionmixture was heated to 110° C. for 24 h, and then cooled to roomtemperature and finally quenched with water (200 mL). The resultingmixture was extracted with EtOAc (3×100 mL), and the extract was dried(MgSO₄), filtered and concentrated under vacuum. Purification by columnchromatography (EtOAc in hexanes gradient) to give 60 (0.9 g, 3.9 mmol,65%) as a brown oil. IR: 3422, 3357, 1711, 1501 cm⁻¹; ¹H NMR (400 MHz,CDCl₃): δ 6.66-6.60 (m, 3H), 3.35 (br s, 2H), 2.78 (s, 3H), 1.44 (s,6H), 1.25 (s, 6H); ¹³C NMR (101 MHz, CDCl₃): δ 215.8, 139.6, 138.6,132.0, 115.0, 114.5, 112.7, 64.3, 47.7, 31.0, 23.0, 22.9.

The Following Pertains to Scheme 11 General Procedure to Synthesize11a-f

To a stirred solution of 60 (0.2 g, 0.86 mmol) in THF (5 mL), was addeddropwise a series of isocyanates or isothiocyanates (0.86 mmol) in THF(2 mL) at room temperature under a nitrogen atmosphere. The reaction wasstirred until TLC analysis indicate the complete consumption of 60. Thesolvent was evaporated under vacuum, the residue was purified by columnchromatography (EtOAc in hexanes gradient), and the product wascrystallized from ether in pentane (3:7) to afford the 11a-f.

Ethyl 2,2,4-trimethyl-4-pentenoate (61)

A 1-L, three-necked, round-bottomed flask was charged with a mixture ofdiisopropylamine (15.9 g, 21.9 mL, 15.7 mmol) in 200 mL of freshlydistilled THF. Then n-butylllithium (2.5 M, 63.0 mL, 157.5 mmol) wasadded to the solution. After about 5 min, ethyl isobutyrate (14.0 g,120.5 mmol) was added dropwise. Stirring was continued for 1 h at −70°C. A solution of 3-iodo-2-methylpropene (21.9 g, 12.9 mL, 120.5 mmol) in100 mL of THF was added dropwise, and the mixture was stirred overnightwith warming to room temperature. The reaction mixture was poured into amixture of ice and 1 M HCl, and the product was extracted with ether(3×100 mL). The combined ether extracts were washed with saturated NaCl,dried (MgSO₄), filtered, and concentrated. Vacuum distillation afforded61 (12.8 g, 64%) as a colorless liquid, bp 50° C. (1.8 mm). IR: 3078,1729, 1645, 895 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 4.79 (s, 1H), 4.65 (s,1H), 4.08 (q, J=7.1 Hz, 2H), 2.31 (s, 2H), 1.66 (s, 3H), 1.25 (t, J=7.1Hz, 3H), 1.17 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 177.7, 142.3, 113.9,60.1, 48.2, 41.7, 25.4, 23.3, 13.9. 2,2,4-Trimethyl-4-pentenoic acid(62)

A 250-mL, round-bottomed flask was charged with 61 (11.2 g, 66.6 mmol)in 25 mL of MeOH, 20% NaOH (30 mL), and the mixture was refluxedovernight at 60-70° C. After cooling to room temperature, 50 mL of waterwas added, and the mixture was acidified with 1 M HCl. The product wasextracted with ether (3×100 mL), and the combined ether extracts werewashed with saturated NaCl, dried (MgSO₄), filtered, and concentrated.Vacuum distillation afforded acid 62 (9.04 g, 96%) as a colorlessliquid, bp 83° C. (1.8 mm). IR: 3077, 1703, 1644, 895 cm⁻¹; ¹H NMR (300MHz, CDCl₃): δ 11.2 (s, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 2.34 (s, 2H),1.71 (s, 3H), 1.21 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 185.3, 142.6,114.8, 48.5, 42.3, 25.7, 23.9.

2,4-Dimethyl-4-penten-2-amine (63)

A 100-mL, three-necked, round-bottomed flask was charged with 62 (2.2 g,15.6 mmol) and TEA (2.9 g, 4.0 mL, 28.6 mmol) in 25 mL of dry benzene.The flask was cooled to 0° C. (ice bath), and diphenyl phosphoryl azide(6.3 g, 23.2 mmol) was added dropwise with stirring. The reactionmixture was stirred at 0° C. for 1 h, then at room temperature for 1 h,and finally at reflux for 3 h (N₂ evolved). The solution was cooled,ether (250 mL) was added, and the organic layer was washed three timeswith water. The organic layer was dried (Na₂SO₄), filtered, andconcentrated. To the concentrated residue was added a mixture of 15% HCl(10 mL) and AcOH (10 mL), and the mixture was stirred overnight at roomtemperature. Water was added, and the aqueous layer was washed withether (3×50 mL). The aqueous layer was cooled (ice bath), basified bydropwise addition of 10% NaOH solution, and the product was extractedwith ether (3×50 mL). The combined ether extracts were washed withwater, saturated NaCl, and then dried (KOH). The solvent was evaporatedto give 63 (1.2 g, 72%) as a light yellow liquid, which was used withoutpurification in the next step. IR: 3355, 2967, 1639, 891 cm⁻¹; ¹H NMR(300 MHz, CDCl₃): δ 4.91 (s, 1H), 4.72 (s, 1H), 2.10 (s, 2H), 1.82 (s,3H), 1.32 (br s, 2H), 1.13 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 143.4,114.8, 52.8, 46.5, 31.3, 25.5.

N-(2,4-Dimethyl-4-penten-2-yl)-4-nitroaniline (64)

A 35-mL Chemglass pressure vessel (No. CG-1880-02), equipped with amagnetic stirrer, was charged with the amine 63 (2.2 g, 19.7 mmol) and1-fluoro-4-nitrobenzene (2.5 g, 17.7 mmol) in DMSO (15 mL). The vesselwas sealed under nitrogen and heated at 80° C. for 48 h. After coolingto room temperature, water was added, and the product was extracted withether (3×75 mL). The combined extracts were washed with water andsaturated NaCl, dried (Na₂SO₄), filtered and concentrated to give ayellow oil, which was chromatographed using 5-15% ether in hexane toafford 64 (1.8 g, 45%) as a yellow oil. IR: 3379, 1599, 1531, 1368, 834cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=9.3 Hz, 2H), 6.61 (d, J=9.3Hz, 2H), 4.94 (s, 1H), 4.72 (s, 1H), 4.63 (br s, 1H), 2.46 (s, 2H), 1.76(s, 3H), 1.44 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 152.7, 142.2, 136.3,126.6, 116.3, 113.3, 54.3, 48.4, 28.8, 24.9.

N-(2,2,4-Trimethyl-4-penten-2-yl)-N-methyl-4-nitroaniline (65)

A system was charged with 64 (70 mg, 0.3 mmol) in 5 mL of DMF. Sodiumhydride (50 mg, 2 mmol) was added, and the mixture was stirred for 5min, and then methyl iodide (3.0 g, 0.6 mmol) was added dropwise.Stirring was continued overnight at room temperature. Aqueous NH₄Cl (5mL) was added, and the product was extracted with ether (3×10 mL). Theether extracts were washed with water and saturated NaCl, dried (MgSO₄),filtered, and concentrated to give a yellow oil, which waschromatographed using 10-20% ether in hexane to afford 65 (70 mg, 99%)as a yellow oil. IR: 1591, 1502, 1307, 837 cm⁻¹; ¹H NMR (300 MHz,CDCl₃): δ 8.06 (d, J=9.3 Hz, 2H), 6.95 (d, J=9.3 Hz, 2H), 4.91 (s, 1H),4.75 (s, 1H), 3.02 (s, 3H), 2.47 (s, 2H), 1.72 (s, 3H), 1.41 (s, 6H);¹³C NMR (75 MHz, CDCl₃): δ 156.6, 142.7, 137.4, 124.8, 119.7, 115.5,59.6, 47.2, 37.5, 28.6, 24.6.

N¹-(2,2,4-Trimethyl-4-penten-2-yl)-N¹-methyl-1,4-benzenediamine (66)

A 250-mL round-bottomed flask was charged with 65 (2.0 g, 8.1 mmol),iron powder (3.0 g, 53.7 mmol, >100 mesh) and NH₄Cl (1.0 g, 18.6 mmol)in 100 mL of EtOH:H₂O (3.6:1). The mixture was heated to 85° C. under N₂for 2 h. The reaction mixture was filtered through CELITE, treated withsaturated NaHCO₃ (100 mL), and extracted with EtOAc (3×100 mL). Thecombined extracts were washed with saturated NaCl, dried (Na₂SO₄),filtered, and concentrated to afford a brown residue (1.67 g, 95%),which was spectroscopically pure and used directly for the next reactionstep. IR: 3348, 1551 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 6.97 (d, J=7.8 Hz,2H), 6.58 (d, J=8.7 Hz, 2H), 4.84 (s, 1H), 4.71 (s, 1H), 3.81 (s, 2H),2.72 (s, 3H), 2.22 (s, 2H), 1.81 (s, 3H), 1.06 (s, 6H); ¹³C NMR (75 MHz,CDCl₃): δ 144.1, 143.5, 129.5, 115.0, 114.6, 113.5, 58.2, 46.5, 37.3,25.7, 25.3.

N-[4-(2,4-Dimethyl-4-penten-2-yl)methylamino)phenyl]acetamide (67)

To a mixture of 66 (1.0 g, 4.7 mmol) in pyridine (20 mL) in a 200-mLround-bottomed flask was added dropwise acetyl chloride (3.3 g, 3.0 mL,42.1 mmol). The mixture was stirred at room temperature for 2-3 h. Thecrude reaction mixture was added to water (100 mL), and the product wasextracted with ether (3×50 mL). The combined ether extracts were washedwith saturated NaCl, dried (MgSO₄), filtered, and concentrated, to givea brown residue, which was purified by chromatography using 30% ether inhexane to afford 67 (1.2 g, 97%) as a light yellow solid, mp 74-75° C.IR: 3297, 1663, 887 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.45 (s, 1H), 7.37(d, J=7.1 Hz, 2H), 7.09 (d, J=7.1 Hz, 2H), 4.86 (s, 1H), 4.73 (s, 1H),2.75 (s, 3H), 2.23 (s, 2H), 2.15 (s, 3H), 1.82 (s, 3H), 1.08 (s, 6H);¹³C NMR (75 MHz, CDCl₃): δ 168.7, 147.6, 143.9, 134.3, 128.8, 120.0,114.7, 58.1, 46.6, 37.1, 26.0, 25.2, 24.8.

N-(1,2,2,4,4-Pentamethyl-1,2,3,4-tetrahydroquinolin-6-yl)acetamide (68)

A modified procedure of Faure (Faure, R., Pommier, A.; Pons, J. M.;Michel Rajzmann, M.; Santelli, M. Formation of 2-cyclohexenoes byFriedel-Crafts acylation of alkenes with β, γ-ethylenic acyl halides,Tetrahedron, 1992, 48, 8419-8430) was followed. A mixture of AlCl₃ (5.0g, 37.4 mmol) in 75 mL of DCM in a 200-mL, three-necked, round-bottomedflask was cooled at −78° C. (dry ice/acetone). Amide 27 (0.9 g, 3.4mmol) in 15 mL of DCM was added dropwise. Stirring was continuedovernight with gradual warming to room temperature. The process wasmonitored by TLC. The reaction mixture was poured onto crushed ice, andthe aqueous phase was extracted with DCM (3×50 mL). The combined organicextracts were washed with saturated NaHCO₃, water, and saturated NaCl,dried (MgSO₄), filtered, and concentrated to give a brown residue, whichwas chromatographed using 5-20% EtOAc in hexane to afford semisolid 68(0.45 g, 53%). IR: 3289, 1655, 1610, 806 cm⁻¹; ¹H NMR (300 MHz, CDCl₃):δ 8.08 (s, 1H), 7.28-7.22 (m, 2H), 6.52 (d, J=8.2 Hz, 1H), 2.72 (s, 3H),2.08 (s, 3H), 1.74 (s, 2H), 1.26 (s, 3H), 1.19 (s, 3H); ¹³C NMR (75 MHz,CDCl₃): δ 169.0, 142.9, 134.4, 128.3, 125.4, 123.8, 120.1, 112.6, 54.5,53.2, 32.8, 31.7, 31.5, 27.8, 24.5.

1,2,2,4,4-Pentamethyl-1,2,3,4-tetrahydroquinolin-6-amine (69)

A 25-mL, round-bottomed flask was charged with amide 68 (0.15 g, 0.6mmol) and 10 mL of 70% (v/v) of H₂SO₄, and the mixture was refluxedovernight. After cooling to room temperature, 10 mL of water was added,and the mixture was basified with 30% NaOH. The amine was extracted withEtOAc (3×15 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated to give 69 (0.15 g, 92%) as a brown residue.This compound was used without further purification. IR: 3336, 1623cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 6.64 (s, 1H), 6.50 (s, 2H), 3.64 (s,2H), 2.69 (s, 3H), 1.74 (s, 2H), 1.28 (s, 6H), 1.17 (s, 6H); ¹³C NMR (75MHz, CDCl₃): δ 139.3, 137.2, 135.8, 114.7, 114.2, 114.0, 53.4, 32.1,31.7, 27.4 (several signals overlap).

The Following Pertains to Scheme 126-Amino-1,2,2,4,4-pentamethyltetrahydroquinolin-3-ol (70)

To a stirred solution of 60 (0.2 g, 0.86 mmol) in THF (10 mL) was addedportion-wise lithium aluminum hydride (65.0 mg, 1.72 mmol) at 0° C. Thereaction was stirred at room temperature for 4 h, quenched withsaturated Na₂SO₄ at 0° C., filtered through CELITE® and extracted withEtOAc (20 mL). The organic layer was washed with water, saturated NaCl,dried (Na₂SO₄), filtered and concentrated to give 70 as a brown oil. Theresidue was dissolved in THF (5 mL), and the solution was added dropwiseat room temperature to an iso(thio)cyanate (0.86 mmol) in THF. When TLCanalysis indicated the disappearance of 70, the reaction mixture wasconcentrated under vacuum and purified by column chromatography (EtOAcin hexanes gradient). Concentration of the major fraction andcrystallization from DCM/ether mixture (2:8) afforded 13a-f.

The Following Pertains to Scheme 13N-(4-(2-Methyl-4-oxopentan-2-yl)thio)phenyl)acetamide (72)

To a stirred solution of acetamidothiophenol (25.0 g, 149.7 mmol) in dryCHCl₃ (20 mL) was added triethylamine (15.1 g, 20.8 mL, 149.7 mmol),followed by mesityl oxide (71, 14.7 g, 17.1 mL, 149.7 mmol). Theresulting slurry was heated to reflux at 70° C. Two additional portionsof triethylamine (7.5 g, 10.4 mL, 74.5 mmol) and 71 (7.4 g, 8.6 mL, 74.5mmol) were added at regular intervals of 4 h, and the resulting solutionwas refluxed for 16 h after the final addition. The resulting reactionmixture was cooled, filtered through CELITE® and washed with chloroform(2×50 mL). The combined organic layers were washed with water (2×100mL), saturated NaCl solution, dried (MgSO₄), filtered and concentratedunder vacuum to give a yellow oil. The crude reaction mixture was thenpurified by silica gel column chromatography eluted with DCM:EtOAc (1:1)to afford 72 as a pale yellow solid, mp 49-51° C. (lit [5] mp 46-49°C.); IR: 3310, 1699, 1676 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.90 (br s,1H, NH), 7.53 (d, 1H, J=8.8 Hz, 2H, Ar—H), 7.45 (d, J=8.8 Hz, 2H, Ar—H),2.65 (s, 2H, CH₂), 2.19 (s, 3H, CH₃), 2.15 (s, 3H, CH₃), 1.36 (s, 6H,2CH₃); ¹³C NMR (101 MHz, CDCl₃): δ 206.9, 168.6, 139.0, 138.3, 126.2,119.6, 54.3, 47.0, 32.1, 28.0, 24.5.

N-{4-[(4-Hydroxy-2,4-dimethylpentan-2-yl)thio]phenyl}acetamide (73)

To a stirred solution of methyllithium in Et₂O (198 mL, 317 mmol, 1.6 M)in THF (300 mL) at −50° C. was added dropwise a solution of 72 (28 g,105.7 mmol) in THF (200 mL) over 30-45 min. The reaction formed a whiteprecipitate and the reaction was slowly warmed to room temperature overa period of 3 h. Stirring was continued at room temperature for 1 h. Thereaction was then cooled to 0° C., and the mixture was quenched bydropwise addition of ice water (150 mL). After adjusting the solution pHto 6-7 by addition of 6 M HCl, the solution was extracted with EtOAc(2×250 mL). The combined organic extracts were washed with saturatedNaCl (1×150 mL), dried (MgSO₄), filtered and concentrated under vacuumto afford a dark brown liquid. To the crude product was added CHCl₃ (60mL) with cooling to 0° C. for 1 h which afforded a yellow solid. Thesolid was then filtered and dried under vacuum to afford 73 (18 g, 61%)as a pale yellow solid, mp 141-142° C. (lit⁵ mp 138-144° C.); IR: 3400,3303, 1676 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.68 (br s, 1H, NH), 7.52(m, 4H, Ar—H), 3.50 (br s, 1H, OH), 2.19 (s, 3H, CH₃), 1.77 (s, 2H,CH₂), 1.34 (s, 6H, 2CH₃), 1.33 (s, 6H, 2CH₃); ¹³C NMR (101 MHz, CDCl₃):δ 168.4, 138.8, 138.1, 126.3, 119.6, 72.0, 52.0, 49.2, 32.2, 30.8, 24.6.

N-(2,2,4,4-Tetramethylthiochroman-6-yl)acetamide (74)

To a stirred solution of 73 (18.0 g, 64.1 mmol) in chlorobenzene (125mL) at 60° C. anhydrous aluminum chloride (10.2 g, 76.7 mmol) was addedportion-wise over a period of 45 min (Caution: This addition wasexothermic and typically raised the temperature of the solvent to itsboiling point. External heating was discontinued before adding thealuminum chloride). Once the addition was complete, heating wascontinued at reflux for an additional 90 min. The reaction mixture wascooled to room temperature and quenched with ice cold water (150 mL) togive a thick suspension. The solid was removed by filtration throughCELITE® and washed with EtOAc (2×100 mL). The layers were separated, andthe aqueous layer was extracted with additional EtOAc (2×100 mL). Thecombined organic extracts were washed with saturated NaCl, dried(MgSO₄), filtered and concentrated under vacuum to give a yellow oil.The crude product was purified on a silica gel column using hexanes:EtOAc (1:1) to afford product 74 (15.0 g, 89%) as a pale yellow solid,mp 105-107° C. (lit⁵ mp 104-107° C.); IR: 3295, 1662 cm⁻¹; ¹H NMR (400MHz, CDCl₃): δ 7.60 (br s, 1H, NH), 7.27 (d, J=2.3 Hz, 1H, Ar—H), 7.20(dd, J=8.2, 2.3 Hz, 1H, Ar—H), 7.04 (d, J=8.2 Hz, 1H, Ar—H), 2.16 (s,3H, CH₃), 1.92 (s, 2H, CH₂), 1.39 (s, 6H, 2CH₃), 1.35 (s, 6H); ¹³C NMR(101 MHz, CDCl₃): δ 168.3, 143.4, 135.1, 128.4, 128.2, 118.7, 118.2,54.4, 42.0, 35.7, 32.4, 31.4, 24.4.

2,2,4,4-Tetramethylthiochroman-6-amine Hydrochloride (75)

To a stirred solution of 74 (15.0 g, 57.0 mmol) in MeOH (25 mL) wasadded 12 M HCl (100 mL) and the mixture was heated to 90° C. for 1 h.The reaction mixture was cooled, and concentrated to 1/4 of its initialvolume. The resulting crude mixture was cooled to 0° C. (ice bath) for 1h to yield a white solid. The solid was filtered and dried under vacuumto afford 75 as a white powder (14.0 g, 95%), mp 208-209° C.; IR: 2922,2853 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 10.08 (s, 2H, NH₂), 7.48 (s, 1H,Ar—H), 7.22 (d, J=8.3 Hz, 1H, Ar—H), 7.09 (d, J=8.3 Hz, 1H, Ar—H), 1.94(s, 2H, CH₂), 1.42 (s, 6H, 2CH₃), 1.40 (s, 6H, 2CH₃); ¹³C NMR (101 MHz,DMSO-d₆): δ 144.2, 132.0, 130.0, 129.1, 122.0, 121.2, 53.5, 42.6, 35.8,32.6, 31.6.

6-Isothiocyanato-2,2,4,4-tetramethylthiochroman (76)

To a stirred solution of 75 10 g, 38.8 mmol) in EtOH (20 mL), CS₂ (29.0g, 22.9 mL, 381 mmol) was added followed by Et₃N (8.03 g, 11.1 mL, 79.5mmol). The reaction mixture was stirred for a period of 20 min followedby the addition of (Boc)₂O (8.46 g, 38.8 mmol) dissolved in ethanol (5mL). To this reaction, DABCO (0.130 g, 1.2 mmol, 3 mol %) in EtOH (2 mL)was added immediately and the reaction mixture was kept in an ice bathfor 10 min, followed by stirring the reaction mixture at roomtemperature for 20 min. The reaction mixture was concentrated undervacuum. The reaction was dissolved in Et₂O (3×100 mL) and washed withsaturated NaCl (50 mL). The organic layer was dried (MgSO₄), filteredand concentrated to dryness. The compound was further purified on asilica gel column eluted with increasing concentrations of EtOAc inhexanes to afford isocyanate 76 (9.40 g, 92%) as a white solid, mp192-193° C.; IR: 2140 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 7.50 (s, 1H,Ar—H), 7.32 (d, J=8.3 Hz, 1H, Ar—H), 7.24 (d, J=8.3 Hz, 1H, Ar—H).

Synthesis of Compounds Shown in Scheme 14

Utilizing the key intermediate 77, the free base of 75, members of 14could be realized. The one-step process in Scheme 14 involved acondensation of 77 with a variety of isocyanates and isothiocyanates togenerate a variety of substituted members of 14.

Synthesis of Compounds Shown in Scheme 15, Including Special Synthesisof Desmethyl Representative (14v)N-(4-((3-Methylbut-2-en-1-yl)thio)phenyl)acetamide (78)

To a stirred solution of acetamidothiphenol (7, 5.0 g, 30.0 mmol) inacetone (25 mL), K₂CO₃ (8.26 g, 60.0 mmol) was added followed by theaddition of 1-bromo-3-methylbut-2-ene (5.51 g, 36.5 mmol) and themixture was refluxed for 6 h. The reaction was concentrated to dryness,the residue was extracted with EtOAc (3×50 mL), the extracts were washedwith saturated NaCl (50 mL), dried (MgSO₄), filtered and concentrated.The crude product was purified on a silica gel column eluted withincreasing concentrations of EtOAc in hexanes to obtain pure 78 (5.9 g,84%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.43 (d, J=8.3 Hz,2H, Ar—H), 7.30 (d, J=8.3 Hz, 2H, Ar—H), 5.27 (t, J=7.6 Hz, 1H, ═CHCH₂),3.49 (d, J=7.6 Hz, 2H, ═CHCH₂), 2.17 (s, 3H, CH₃CO), 1.54 (s, 3H, CH₃),1.20 (s, 3H, CH₃) (NH missing); ¹³C NMR (101 MHz, CDCl₃): δ 168.4,136.5, 136.3, 131.7, 131.5, 120.2, 119.4, 33.1, 25.7, 24.6, 17.7.

N-(4,4-Dimethylthiochroman-6-yl)acetamide (79)

To stirred polyphosphoric acid (10 g) at 70° C., 78 (4.00 g, 17.0 mmol)was added and heating was continued for 2 h. The reaction mixture wascooled at 0° C., poured into ice-cold water and stirred for 2 h. Thecompound was extracted with EtOAc (3×50 mL), washed with saturatedNaHCO₃ (100 mL), saturated NaCl (50 mL), dried (MgSO₄), filtered andconcentrated under vacuum. The product was purified on a silica gelcolumn eluted with increasing concentrations of EtOAc in hexanes to give79 (2.88 g, 72%) as a colorless liquid. IR: 3305, 1662 cm⁻¹; ¹H NMR (400MHz, CDCl₃): δ 7.60 (br s, 1H, NH), 7.27 (d, J=2.3 Hz, 1H, Ar—H), 7.20(dd, J=8.2, 2.3 Hz, 1H, Ar—H), 7.04 (d, J=8.2 Hz, 1H, Ar—H), 2.16 (s,3H, CH₃CO), 2.72 (t, J=4.1 Hz, 2H, CH₂), 1.90 (t, J=4.1 Hz, 2H, CH₂S),1.39 (s, 6H, 2CH₃); ¹³C NMR (101 MHz, CDCl₃): δ 168.3, 143.4, 135.1,128.4, 128.2, 118.7, 118.2, 54.4, 35.7, 32.4, 24.4. 20.1.

4,4-Dimethylthiochroman-6-amine hydrochloride (80)

To a stirred solution of 79 (2.7 g, 11.5 mmol) in methanol (15 mL) wasadded 6 M HCl (15 mL). The reaction mixture was heated to 90° C. for 1h, followed by cooling to room temperature. The reaction wasconcentrated to 1/4 of its initial volume and then was cooled to 0° C.for 1 h to yield a solid. The solid was filtered and dried under vacuumto afford 80 as an off-white solid (2.27 g, 86%), mp 214-216° C.; IR:2926, 2794 cm⁻¹; ¹H NMR (DMSO-d₆): δ 10.08 (s, 2H, NH₂), 7.48 (s, 1H,Ar—H), 7.22 (d, J=8.3 Hz, 1H, Ar—H), 7.09 (d, J=8.3 Hz, 1H, Ar—H), 2.70(t, J=4.1 Hz, 2H, CH₂S) 1.94 (t, J=4.1 Hz, 2H, CH₂), 1.40 (s, 6H, 2CH₃);¹³C NMR (DMSO-d₆): δ 144.2, 132.0, 130.0, 129.1, 122.0, 121.2, 53.5,42.6, 35.8, 20.4.

1-(4,4-dimethyl-6-yl)-3-(4-nitrophenyl)thiourea (14v)

Neutralization of the salt 80 gave the free base. The free base (0.100g, 0.44 mmol) in THF:DCM (1:1, 5 mL) was treated with4-nitrophenylisothiocyanate (0.46 mmol), followed by Et₃N (0.53 mmol,0.54 g, 74 μL, 1.2 equiv.). The mixture was stirred at 23° C. for 18 hand was then decomposed. Separation of the organic phase gave a residewhich was concentrated and then subjected to chromatography on silicagel with increasing concentrations of EtOAc in hexanes to yield 14v as alight yellow solid (0.134 g, 82%), mp 142-143° C.; ¹H NMR (400 MHz,DMSO-d₆): δ 10.34 (s, 1H, NH), 10.20 (s, 1H, NH), 8.20 (d, J=8.8 Hz, 2H,Ar—H), 7.83 (d, J=8.8 Hz, 2H, Ar—H), 7.54 (s, 1H, Ar—H), 7.20 (d, J=8.4Hz, 1, Ar—H), 7.01 (d, J=8/5 Hz, 1H, Ar—H), 3.02 (d, J=6.0 Hz, 2H,CH₂S), 1.89 (d, J=6.0 Hz, 2H, CH₂), 1.26 (s, 6H, 2 CH₃); ¹³C NMR (101MHz, DMSO-d₆): δ 179.4, 146.8, 142.7, 142.4, 135.6, 128.3, 126.5, 124.9,122.8, 122.4, 121.9, 37.4, 33.3, 30.4, 22.8. Anal. Calcd. forC₁₈H₁₉N₃O₂,S₂: C, 57.89; H, 5.13; N, 11.25. Found: C, 58.02; H, 5.26; N,11.32.

Example 4

Non small cell lung cancer (NSCLC) is especially difficult to treat withKEYTRUDA® (pembrolizumab)(www.keytruda.com/non-small-cell-lung-cancer/monotherapy), OPDIVO®(nivolumab) (www.opdivo.com/advanced-nscle?utm_source=google), orZYKADIA® (ceritinib) (www.zykadia.com/patient-support/financial). Manyside effects occur with these clinical agents. Thus, new agents areneeded.

Several compounds related to SHetA2 have exhibited strong activityagainst Non-Small Cell Lung Cancer (NSCLC) [Yi-D Lin, S. Chen, P. Yue,W. Zou, D. et. al. Cancer Res. 2008, 68, 5335-5344. Y. Lin, X. Lui, P.Yue, D. M. Benbrook, et. al. Molecular Cancer Therapeutics. 2008, 7,3556-3565.] When tested using methods known to those of skill in theart, the new compounds disclosed herein also kill NSCLC cancer cells anddisplay activity against lung cancer.

While this invention is susceptible of embodiment in many differentforms, there is shown in the drawings, and will herein be describedhereinafter in detail, some specific embodiments of the instantinvention. It should be understood, however, that the present disclosureis to be considered an exemplification of the principles of theinvention and is not intended to limit the invention to the specificembodiments or algorithms so described.

It is to be understood that the terms “including”, “comprising”,“consisting” and grammatical variants thereof do not preclude theaddition of one or more components, features, steps, or integers orgroups thereof and that the terms are to be construed as specifyingcomponents, features, steps or integers.

If the specification or claims refer to “an additional” element, thatdoes not preclude there being more than one of the additional element.

It is to be understood that where the claims or specification refer to“a” or “an” element, such reference is not be construed that there isonly one of that element.

It is to be understood that where the specification states that acomponent, feature, structure, or characteristic “may”, “might”, “can”or “could” be included, that particular component, feature, structure,or characteristic is not required to be included.

Where applicable, although state diagrams, flow diagrams or both may beused to describe embodiments, the invention is not limited to thosediagrams or to the corresponding descriptions. For example, flow neednot move through each illustrated box or state, or in exactly the sameorder as illustrated and described.

Methods of the present invention may be implemented by performing orcompleting manually, automatically, or a combination thereof, selectedsteps or tasks.

The term “method” may refer to manners, means, techniques and proceduresfor accomplishing a given task including, but not limited to, thosemanners, means, techniques and procedures either known to, or readilydeveloped from known manners, means, techniques and procedures bypractitioners of the art to which the invention belongs.

For purposes of the instant disclosure, the term “at least” followed bya number is used herein to denote the start of a range beginning withthat number (which may be a range having an upper limit or no upperlimit, depending on the variable being defined). For example, “at least1” means 1 or more than 1. The term “at most” followed by a number isused herein to denote the end of a range ending with that number (whichmay be a range having 1 or 0 as its lower limit, or a range having nolower limit, depending upon the variable being defined). For example,“at most 4” means 4 or less than 4, and “at most 40%” means 40% or lessthan 40%. Terms of approximation (e.g., “about”, “substantially”,“approximately”, etc.) should be interpreted according to their ordinaryand customary meanings as used in the associated art unless indicatedotherwise. Absent a specific definition and absent ordinary andcustomary usage in the associated art, such terms should be interpretedto be ±10% of the base value.

When, in this document, a range is given as “(a first number) to (asecond number)” or “(a first number)-(a second number)”, this means arange whose lower limit is the first number and whose upper limit is thesecond number. For example, 25 to 100 should be interpreted to mean arange whose lower limit is 25 and whose upper limit is 100.Additionally, it should be noted that where a range is given, everypossible subrange or interval within that range is also specificallyintended unless the context indicates to the contrary. For example, ifthe specification indicates a range of 25 to 100 such range is alsointended to include subranges such as 26-100, 27-100, etc., 25-99,25-98, etc., as well as any other possible combination of lower andupper values within the stated range, e.g., 33-47, 60-97, 41-45, 28-96,etc. Note that integer range values have been used in this paragraph forpurposes of illustration only and decimal and fractional values (e.g.,46.7-91.3) should also be understood to be intended as possible subrangeendpoints unless specifically excluded.

It should be noted that where reference is made herein to a methodcomprising two or more defined steps, the defined steps can be carriedout in any order or simultaneously (except where context excludes thatpossibility), and the method can also include one or more other stepswhich are carried out before any of the defined steps, between two ofthe defined steps, or after all of the defined steps (except wherecontext excludes that possibility).

Furthermore, it should be noted that terms of approximation (e.g.,“about”, “substantially”, “approximately”, etc.) are to be interpretedaccording to their ordinary and customary meanings as used in theassociated art unless indicated otherwise herein. Absent a specificdefinition within this disclosure, and absent ordinary and customaryusage in the associated art, such terms should be interpreted to be plusor minus 10% of the base value.

Still further, additional aspects of the instant invention may be foundin one or more appendices attached hereto and/or filed herewith, thedisclosures of which are incorporated herein by reference as if fullyset out at this point.

Thus, the present invention is well adapted to carry out the objects andattain the ends and advantages mentioned above as well as those inherenttherein. While the inventive device has been described and illustratedherein by reference to certain preferred embodiments in relation to thedrawings attached thereto, various changes and further modifications,apart from those shown or suggested herein, may be made therein by thoseof ordinary skill in the art, without departing from the spirit of theinventive concept the scope of which is to be determined by thefollowing claims.

REFERENCES

-   Waugh, K. M.; Berlin, K. D.; Ford, W. T.; Holt, E. M.; Carroll, J.    P.; Schomber, P. R.; Schiff, L. J. Synthesis and characterization of    selected heteroarotinoids. Pharmacological activity as assessed in    vitamin A deficient hamster tracheal organ cultures. Single crystal    X-ray diffraction analysis of    1-(1-1-dioxa3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethanone    and ethyl    (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl]benzoate. J.    Med. Chem. 1985, 27, 116-124; Spruce, L. W.; Rajadhyaksha, S. N.;    Berlin, K. D.; Gale, J. B.; Miranda, E. T.; Ford, W. T.; Blossey, E.    C.; Verma, A. K.; Hossain, M. B. van der Helm, D.; Breitman, T. R.    Heteroarotinoids. Synthesis, characterization and biological    activity in terms of an assessment of these systems to inhibit    induction of ornithine decarboxylase activity and to induce terminal    differentiation of HL-60 cells. J. Med. Chem. 1987, 30, 1474-1482;    Gale, J. B.; Rajadhyaksha, S. N.; Spruce, L. W.; Berlin, K. D.; Ji,    X.; Slagle, A.; van der Helm, D. Heteroarotinoids: Analytical    criteria for the rapid identification of (F)- and (Z)-isomers of    these novel retinoids via NMR, UV, and X-ray analyses of selected    examples. J. Org. Chem. 1990, 55, 3984-3991; Spruce, L. W.; Gale, J.    B.; Berlin, K. D.; Verma, A. K.; Breitman, T. R.; Ji, X.; van der    Helm, D. Novel Heteroarotinoids: Synthesis and biological    activity. J. Med. Chem. 1991, 34, 430-439; Benbrook, D. M.;    Madler, M. M.; Spruce, L. W.; Birckbichler, P. J.; Nelson, E, C.;    Subramanian, S.; Weerasekare, G. M.; Gale, J. B.; Patterson, Jr., M.    K.; Wang, B.; Wang, W.; Lu, S.; Rowland, T. C.; DiSivestro, P.;    Lindamood, C.; Hill, D. L.; and Berlin, K. D. Biologically active    heteroarotinoids exhibit anticancer activity and decreased    toxicity. J. Med. Chem. 1997, 40, 3567-3583; Benbrook, D. M.;    Subramanian, S.; Gale, J. B.; Liu, S.; Brown, C. W.; Boehm, M. F.;    Berlin, K. D. Synthesis and characterization of heteroarotinoids    demonstrates structure-activity relationships. J. Med. Chem. 1998,    41, 3753-3757; Dhar, A.; Liu, S.; Klucik, J.; Berlin, K. D.;    Madler, M. M.; Lu, S.; Ivey, R. T.; Zacheis, D.; Brown, C. W.;    Nelson, E. C.; Birckbichler, P. J.; Benbrook, D. M. Synthesis,    structure-activity relationships, and RAR-γ-ligand interactions of    nitrogen heteroarotinoids. J. Med. Chem. 1999, 42, 3602-3614.

What is claimed is:
 1. A method of treating cancer in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of compound of Formula I

wherein, R₁ and R₂ are optionally C1-C5 substituted alkyl; R₃ and R₄ areoptionally C1-C5 substituted alkyl; G is CH₂, C═O or CHOH; X is S, O, NRor N⁺(R)₂ where R is hydrogen or an optionally substituted C1-C5 alkyl;R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl; Y is O orS; and Z is an optionally substituted phenyl, optionally substitutedphenylamino or optionally substituted benzylamide; and salts, solvatesand hydrates thereof, with the caveat that the compound is not ShetA2with the formula


2. The method of claim 1, wherein the compound is:


3. The method of claim 1, wherein the cancer is ovarian cancer or smallcell lung cancer.
 4. A method of killing cancer cells, comprisingcontacting the cells with an amount of a compound of Formula I

wherein, R₁ and R₂ are optionally C1-C5 substituted alkyl; R₃ and R₄ areoptionally C1-C5 substituted alkyl; G is CH₂, C═O or CHOH; X is S, O, NRor N⁺(R)₂ where R is hydrogen or an optionally substituted C1-C5 alkyl;R₅ and R₆ are hydrogen or optionally substituted C1-C5 alkyl; Y is O orS; and Z is an optionally substituted phenyl, optionally substitutedphenylamino or optionally substituted benzylamide; and salts, solvatesand hydrates thereof, wherein the amount is sufficient to kill thecancer cells, with the caveat that the compound is not ShetA2 with theformula


5. The method of claim 4, wherein the compound is:


6. The method of claim 4, wherein the cancer cells are ovarian cancercells.